chr12-123712682-CG-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_StrongPM2PP3_ModeratePP5_Moderate
The NM_012463.4(ATP6V0A2):c.117+1del variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
ATP6V0A2
NM_012463.4 splice_donor
NM_012463.4 splice_donor
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.14
Genes affected
ATP6V0A2 (HGNC:18481): (ATPase H+ transporting V0 subunit a2) The protein encoded by this gene is a subunit of the vacuolar ATPase (v-ATPase), an heteromultimeric enzyme that is present in intracellular vesicles and in the plasma membrane of specialized cells, and which is essential for the acidification of diverse cellular components. V-ATPase is comprised of a membrane peripheral V(1) domain for ATP hydrolysis, and an integral membrane V(0) domain for proton translocation. The subunit encoded by this gene is a component of the V(0) domain. Mutations in this gene are a cause of both cutis laxa type II and wrinkly skin syndrome. [provided by RefSeq, Jul 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.12796578 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 12-123712682-CG-C is Pathogenic according to our data. Variant chr12-123712682-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2735988.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP6V0A2 | NM_012463.4 | c.117+1del | splice_donor_variant | ENST00000330342.8 | |||
ATP6V0A2 | XM_024448910.2 | c.117+1del | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP6V0A2 | ENST00000330342.8 | c.117+1del | splice_donor_variant | 1 | NM_012463.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000893 AC: 13AN: 1456346Hom.: 0 Cov.: 32 AF XY: 0.00000828 AC XY: 6AN XY: 724404
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
13
AN:
1456346
Hom.:
Cov.:
32
AF XY:
AC XY:
6
AN XY:
724404
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
Bravo
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
ALG9 congenital disorder of glycosylation Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 14, 2023 | This sequence change affects a splice site in intron 1 of the ATP6V0A2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATP6V0A2 are known to be pathogenic (PMID: 18157129, 19321599). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with cutis laxa (PMID: 22773132). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at