rs17720303

Positions:

chr2-70936043-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001692.4(ATP6V1B1):c.89C>T(p.Thr30Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,613,698 control chromosomes in the GnomAD database, including 24,255 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2144 hom., cov: 32)

Exomes 𝑓: 0.17 ( 22111 hom. )

Consequence

ATP6V1B1
NM_001692.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.75

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]

ATP6V1B1 links:

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]

VAX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016556978).

BP6

Variant 2-70936043-C-T is Benign according to our data. Variant chr2-70936043-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 44231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-70936043-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V1B1	NM_001692.4 linkuse as main transcript	c.89C>T	p.Thr30Ile	missense_variant	1/14	ENST00000234396.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V1B1	ENST00000234396.10 linkuse as main transcript	c.89C>T	p.Thr30Ile	missense_variant	1/14	1	NM_001692.4	P1

Frequencies

GnomAD3 genomes

AF:

0.167

AC:

25401

AN:

151982

Hom.:

2147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.149

Gnomad AMR

AF:

0.219

Gnomad ASJ

AF:

0.220

Gnomad EAS

AF:

0.217

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.161

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.171

Gnomad OTH

AF:

0.186

GnomAD3 exomes

AF:

0.185

AC:

46456

AN:

251060

Hom.:

4706

AF XY:

0.181

AC XY:

24521

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.267

Gnomad ASJ exome

AF:

0.224

Gnomad EAS exome

AF:

0.217

Gnomad SAS exome

AF:

0.151

Gnomad FIN exome

AF:

0.162

Gnomad NFE exome

AF:

0.173

Gnomad OTH exome

AF:

0.187

GnomAD4 exome

AF:

0.172

AC:

251189

AN:

1461598

Hom.:

22111

Cov.:

AF XY:

0.172

AC XY:

124795

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.132

Gnomad4 AMR exome

AF:

0.261

Gnomad4 ASJ exome

AF:

0.225

Gnomad4 EAS exome

AF:

0.208

Gnomad4 SAS exome

AF:

0.154

Gnomad4 FIN exome

AF:

0.160

Gnomad4 NFE exome

AF:

0.168

Gnomad4 OTH exome

AF:

0.180

GnomAD4 genome

AF:

0.167

AC:

25419

AN:

152100

Hom.:

2144

Cov.:

AF XY:

0.167

AC XY:

12383

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.133

Gnomad4 AMR

AF:

0.218

Gnomad4 ASJ

AF:

0.220

Gnomad4 EAS

AF:

0.217

Gnomad4 SAS

AF:

0.160

Gnomad4 FIN

AF:

0.161

Gnomad4 NFE

AF:

0.171

Gnomad4 OTH

AF:

0.187

Alfa

AF:

0.176

Hom.:

2630

Bravo

AF:

0.176

TwinsUK

AF:

0.162

AC:

599

ALSPAC

AF:

0.162

AC:

624

ESP6500AA

AF:

0.140

AC:

619

ESP6500EA

AF:

0.168

AC:

1443

ExAC

AF:

0.180

AC:

21833

Asia WGS

AF:

0.183

AC:

637

AN:

3478

EpiCase

AF:

0.182

EpiControl

AF:

0.179

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Thr30Ile in Exon 01 of ATP6V1B1: This variant is not expected to have clinical s ignificance because it has been identified in 17.0% (1190/7020) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs17720303). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 28, 2016	- -

Renal tubular acidosis with progressive nerve deafness

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

0.0091

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.85

T;T;T

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.99

L;.;.

MutationTaster

Benign

0.00010

P;P

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.5

N;.;N

REVEL

Benign

0.20

Sift

Benign

0.14

T;.;T

Sift4G

Benign

0.066

T;.;T

Polyphen

0.0

B;.;B

Vest4

0.41

MPC

0.33

ClinPred

0.017

GERP RS

4.9

Varity_R

0.18

gMVP

0.36

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over