rs794729667
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_001693.4(ATP6V1B2):c.1516C>T(p.Arg506Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
ATP6V1B2
NM_001693.4 stop_gained
NM_001693.4 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 1.61
Genes affected
ATP6V1B2 (HGNC:854): (ATPase H+ transporting V1 subunit B2) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A, three B, and two G subunits, as well as a C, D, E, F, and H subunit. The V1 domain contains the ATP catalytic site. The protein encoded by this gene is one of two V1 domain B subunit isoforms and is the only B isoform highly expressed in osteoclasts. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.013 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 8-20220382-C-T is Pathogenic according to our data. Variant chr8-20220382-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 203442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-20220382-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP6V1B2 | NM_001693.4 | c.1516C>T | p.Arg506Ter | stop_gained | 14/14 | ENST00000276390.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP6V1B2 | ENST00000276390.7 | c.1516C>T | p.Arg506Ter | stop_gained | 14/14 | 1 | NM_001693.4 | P1 | |
ATP6V1B2 | ENST00000523482.5 | n.5600C>T | non_coding_transcript_exon_variant | 11/11 | 2 | ||||
ATP6V1B2 | ENST00000521442.1 | c.101+2100C>T | intron_variant, NMD_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal dominant deafness - onychodystrophy syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 25, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function has been shown to be a mechanism of disease for this gene (PMID: 24913193). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 14 of 14). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. Other truncating variants downstream of this variant has not been reported (ClinVar, PMID: 31655144). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals where variant has been shown to be de novo. (ClinVar, PMID: 24913193, 28396750, 31581539). (P) 1002 - Moderate functional evidence supporting abnormal protein function, with variant shown to result in reduced ATPase hydrolysis activity (PMID: 24913193). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2014 | - - |
Neurodevelopmental delay Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 06, 2023 | Published functional studies demonstrate a damaging effect; ATPase hydrolysis activity was decreased in cells expressing the R506* variant, and a knock-in mouse model incorporating R506* showed changes in brain composition compared to wild type mice (Yuan et al., 2014; Zhao et al., 2019); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28396750, 34912366, 32849222, 31257146, 32961450, 24913193, 32873933) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at