2-70936045-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001692.4(ATP6V1B1):​c.91C>T​(p.Arg31*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ATP6V1B1
NM_001692.4 stop_gained

Scores

2
3
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: -0.335
Variant links:
Genes affected
ATP6V1B1 (HGNC:853): (ATPase H+ transporting V1 subunit B1) 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 and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c'', and d. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This encoded protein is one of two V1 domain B subunit isoforms and is found in the kidney. Mutations in this gene cause distal renal tubular acidosis associated with sensorineural deafness. [provided by RefSeq, Jul 2008]
VAX2 (HGNC:12661): (ventral anterior homeobox 2) This gene encodes a homeobox protein and is almost exclusively expressed in the ventral portion of the retina during development. In mouse studies, this gene was found to be required for the correct formation of the optic fissure and other aspects of retinal development. [provided by RefSeq, Sep 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 28 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-70936045-C-T is Pathogenic according to our data. Variant chr2-70936045-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-70936045-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP6V1B1NM_001692.4 linkc.91C>T p.Arg31* stop_gained 1/14 ENST00000234396.10 NP_001683.2 P15313

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP6V1B1ENST00000234396.10 linkc.91C>T p.Arg31* stop_gained 1/141 NM_001692.4 ENSP00000234396.4 P15313

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461776
Hom.:
0
Cov.:
37
AF XY:
0.00000413
AC XY:
3
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Renal tubular acidosis with progressive nerve deafness Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 19, 2024- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 1999- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 14, 2024This sequence change creates a premature translational stop signal (p.Arg31*) in the ATP6V1B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP6V1B1 are known to be pathogenic (PMID: 9916796, 18368028). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with renal tubular acidosis with sensorineural deafness (PMID: 9916796, 23923981). ClinVar contains an entry for this variant (Variation ID: 12225). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.47
CADD
Pathogenic
40
DANN
Uncertain
1.0
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Benign
0.56
D
Vest4
0.67
GERP RS
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121964879; hg19: chr2-71163175; COSMIC: COSV52265379; COSMIC: COSV52265379; API