rs2072462

Variant names:

• chr2-70963254-C-T
• rs2072462
• NM_001692.4:c.1002C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001692.4(ATP6V1B1):​c.1002C>T​(p.Arg334Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,613,544 control chromosomes in the GnomAD database, including 172,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12924 hom., cov: 32)
  • Exomes 𝑓: 0.46 (159081 hom.)
• Consequence: ATP6V1B1 NM_001692.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.74

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]

ENSG00000258881 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 2-70963254-C-T is Benign according to our data. Variant chr2-70963254-C-T is described in ClinVar as [Benign]. Clinvar id is 44222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-70963254-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V1B1	NM_001692.4	c.1002C>T	p.Arg334Arg	synonymous_variant	Exon 10 of 14	ENST00000234396.10	NP_001683.2
ATP6V1B1	XM_011532907.3	c.1122C>T	p.Arg374Arg	synonymous_variant	Exon 9 of 13		XP_011531209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V1B1	ENST00000234396.10	c.1002C>T	p.Arg334Arg	synonymous_variant	Exon 10 of 14	1	NM_001692.4	ENSP00000234396.4
ENSG00000258881	ENST00000606025.5	c.476-20821G>A		intron_variant	Intron 5 of 5	5		ENSP00000475641.1

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58766 AN: 151886 Hom.: 12924 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.469

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.657

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.392

GnomAD3 exomes AF: 0.477 AC: 119788 AN: 251080 Hom.: 30220 AF XY: 0.483 AC XY: 65612 AN XY: 135770

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.563

Gnomad ASJ exome AF: 0.512

Gnomad EAS exome AF: 0.654

Gnomad SAS exome AF: 0.588

Gnomad FIN exome AF: 0.394

Gnomad NFE exome AF: 0.449

Gnomad OTH exome AF: 0.482

GnomAD4 exome AF: 0.461 AC: 673324 AN: 1461540 Hom.: 159081 Cov.: 82 AF XY: 0.464 AC XY: 337564 AN XY: 727092

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.549

Gnomad4 ASJ exome AF: 0.509

Gnomad4 EAS exome AF: 0.661

Gnomad4 SAS exome AF: 0.586

Gnomad4 FIN exome AF: 0.402

Gnomad4 NFE exome AF: 0.451

Gnomad4 OTH exome AF: 0.457

GnomAD4 genome AF: 0.387 AC: 58775 AN: 152004 Hom.: 12924 Cov.: 32 AF XY: 0.389 AC XY: 28910 AN XY: 74274

Gnomad4 AFR AF: 0.176

Gnomad4 AMR AF: 0.470

Gnomad4 ASJ AF: 0.521

Gnomad4 EAS AF: 0.656

Gnomad4 SAS AF: 0.575

Gnomad4 FIN AF: 0.396

Gnomad4 NFE AF: 0.453

Gnomad4 OTH AF: 0.393

Alfa AF: 0.445 Hom.: 26616

Bravo AF: 0.383

Asia WGS AF: 0.563 AC: 1956 AN: 3478

EpiCase AF: 0.457

EpiControl AF: 0.460

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg334Arg in Exon 10 of ATP6V1B1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wi thin the splice consensus sequence, and has been identified in 44.6% (3132/7020) of European American chromosomes from a broad population by the NHLBI Exome Seq uencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2072462). -

Renal tubular acidosis with progressive nerve deafness Benign:3

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.5
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs2072462; hg19: chr2-71190384; COSMIC: COSV52270747; COSMIC: COSV52270747;