rs142905621

Variant names:

• chr2-70964973-G-A
• rs142905621
• NM_001692.4:c.1394G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-70964973-G-A
• chr2-70964973-G-C
• chr2-70964973-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_001692.4(ATP6V1B1):​c.1394G>A​(p.Arg465His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,613,912 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R465P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0031 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (29 hom.)
• Consequence: ATP6V1B1 NM_001692.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 10.0
• Publications: 14 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0092583).
• BP6: Variant 2-70964973-G-A is Benign according to our data. Variant chr2-70964973-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178290.We mark this variant Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00307 (468/152266) while in subpopulation SAS AF = 0.0168 (81/4832). AF 95% confidence interval is 0.0138. There are 7 homozygotes in GnomAd4. There are 238 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V1B1	NM_001692.4	c.1394G>A	p.Arg465His	missense_variant	Exon 14 of 14	ENST00000234396.10	NP_001683.2
ATP6V1B1	XM_011532907.3	c.1514G>A	p.Arg505His	missense_variant	Exon 13 of 13		XP_011531209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V1B1	ENST00000234396.10	c.1394G>A	p.Arg465His	missense_variant	Exon 14 of 14	1	NM_001692.4	ENSP00000234396.4
ENSG00000258881	ENST00000606025.5	c.476-22540C>T		intron_variant	Intron 5 of 5	5		ENSP00000475641.1

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 466 AN: 152148 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00760

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00579

Gnomad SAS AF: 0.0163

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00301 AC: 757 AN: 251130 AF XY: 0.00373

Gnomad AFR exome AF: 0.00862

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00413

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00151 AC: 2204 AN: 1461646 Hom.: 29 Cov.: 33 AF XY: 0.00194 AC XY: 1412 AN XY: 727126

African (AFR) AF: 0.00765 AC: 256 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00597 AC: 237 AN: 39700

South Asian (SAS) AF: 0.0153 AC: 1324 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53182

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.000170 AC: 189 AN: 1112006

Other (OTH) AF: 0.00272 AC: 164 AN: 60392

GnomAD4 genome AF: 0.00307 AC: 468 AN: 152266 Hom.: 7 Cov.: 31 AF XY: 0.00320 AC XY: 238 AN XY: 74468

African (AFR) AF: 0.00758 AC: 315 AN: 41546

American (AMR) AF: 0.00118 AC: 18 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00580 AC: 30 AN: 5172

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00130 Hom.: 4

Bravo AF: 0.00277

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00344 AC: 418

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Renal tubular acidosis with progressive nerve deafness Uncertain:1 Benign:5

May 18, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Arg465His variant in ATP6V1B1 has been identified in a German individual with renal tubular acidosis and no other potentially causal variant identified in the gene (PMID: 12579397), but has also been identified in >1% of South Asian chromosomes and 6 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive renal tubular acidosis. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not specified Benign:3

Jan 22, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg465His in Exon 14 of ATP6V1B1: This variant is not expected to have clinical significance because it has been identified in 0.8% (30/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs142905621). -

not provided Benign:3

Jul 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27535533, 12579397, 26920127) -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP6V1B1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	1.0	D;D;D
MetaRNN	Benign	0.0093	T;T;T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.5	H;.;.
PhyloP100		10
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.4	D;D;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.022	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.81
MVP		0.96
MPC		1.1
ClinPred		0.067	T
GERP RS		3.8
Varity_R		0.74
gMVP		0.76
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs142905621; hg19: chr2-71192103;