VCV000018255.7 - ClinVar

NM_001625.4(AK2):c.498+1G>A

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001625.4(AK2):c.498+1G>A

Variation ID: 18255 Accession: VCV000018255.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p35.1 1: 33014521 (GRCh38) [ NCBI UCSC ] 1: 33480122 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 31, 2019	Nov 30, 2024	Nov 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001625.4:c.498+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001199199.3:c.474+1G>A		splice donor
NM_001319139.3:c.354+1G>A		splice donor
NM_001319140.2:c.354+1G>A		splice donor
NM_001319141.3:c.498+1G>A		splice donor
NM_001319142.3:c.372+1G>A		splice donor
NM_001319143.2:c.*1+1G>A		splice donor
NM_013411.5:c.498+1G>A		splice donor
NC_000001.11:g.33014521C>T
NC_000001.10:g.33480122C>T
NG_016269.1:g.27371G>A
LRG_133:g.27371G>A

... more HGVS ... less HGVS

Protein change

Other names

498, G-A, +1

Canonical SPDI

NC_000001.11:33014520:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

OMIM: 103020.0006 dbSNP: rs777503956 VarSome

Comment on variant

ClinGen staff contributed the HGVS expression for this variant.

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
AK2		-	-	GRCh38 GRCh37	179	216

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Reticular dysgenesis	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 27, 2023	RCV000019917.33
Severe combined immunodeficiency disease	Pathogenic (1)	criteria provided, single submitter	Oct 4, 2021	RCV001778659.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 04, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Severe combined immunodeficiency disease Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002015175.1 First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021	Publications: PubMed (2) PubMed: 28331055‚ 19043417 Comment: Variant summary: AK2 c.498+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more) Variant summary: AK2 c.498+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5 prime splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Pannicke_2009). The variant allele was found at a frequency of 1.6e-05 in 251428 control chromosomes. c.498+1G>A has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome (Pannicke_2009, Hoenig_2017). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Nov 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Reticular dysgenesis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002214228.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 19043417‚ 17576681‚ 9536098 Comment: This sequence change affects a donor splice site in intron 5 of the AK2 gene. While this variant is not anticipated to result in nonsense … (more) This sequence change affects a donor splice site in intron 5 of the AK2 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs777503956, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with reticular dysgenesis (PMID: 19043417). ClinVar contains an entry for this variant (Variation ID: 18255). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 19043417). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Reticular dysgenesis Affected status: yes Allele origin: germline	Juno Genomics, Hangzhou Juno Genomics, Inc Accession: SCV005416833.1 First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024	Comment: PM2_Supporting+PVS1_Strong+PM3+PP4
Pathogenic (Jan 01, 2009)	no assertion criteria provided Method: literature only	RETICULAR DYSGENESIS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000040215.2 First in ClinVar: Apr 04, 2013 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 19043417 Comment on evidence: In a Turkish female with reticular dysgenesis (267500), the offspring of consanguineous parents, Pannicke et al. (2009) identified homozygosity for a splicing mutation, 498+1G-A, in … (more) In a Turkish female with reticular dysgenesis (267500), the offspring of consanguineous parents, Pannicke et al. (2009) identified homozygosity for a splicing mutation, 498+1G-A, in the AK2 gene. The mutation led to a complete loss of detectable AK2 protein in fibroblasts and in bone marrow mononuclear cells. The parents were heterozygous for the mutation, which was not found in 112 German or 50 Turkish healthy subjects. (less)

Comment:

Variant summary: AK2 c.498+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5 prime splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Pannicke_2009). The variant allele was found at a frequency of 1.6e-05 in 251428 control chromosomes. c.498+1G>A has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome (Pannicke_2009, Hoenig_2017). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change affects a donor splice site in intron 5 of the AK2 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs777503956, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with reticular dysgenesis (PMID: 19043417). ClinVar contains an entry for this variant (Variation ID: 18255). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 19043417). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Reticular dysgenesis: international survey on clinical presentation, transplantation, and outcome.	Hoenig M	Blood	2017	PMID: 28331055
Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2.	Pannicke U	Nature genetics	2009	PMID: 19043417
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs777503956 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 07, 2024

ClinVar Genomic variation as it relates to human health

NM_001625.4(AK2):c.498+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs777503956 ...