2-70935956-T-C

Position:

chr2-70935956-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBA1

The NM_001692.4(ATP6V1B1):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 1,612,178 control chromosomes in the GnomAD database, including 148,554 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 12699 hom., cov: 32)

Exomes 𝑓: 0.43 ( 135855 hom. )

Consequence

ATP6V1B1
NM_001692.4 start_lost

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.64

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 -8 ACMG points.

PVS1

Start lost variant, no new inframe start found.

BP6

Variant 2-70935956-T-C is Benign according to our data. Variant chr2-70935956-T-C is described in ClinVar as [Benign]. Clinvar id is 44228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-70935956-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V1B1	NM_001692.4 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/14	ENST00000234396.10	NP_001683.2	P15313

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V1B1	ENST00000234396.10 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/14	1	NM_001692.4	ENSP00000234396.4		P15313

Frequencies

GnomAD3 genomes

AF:

0.406

AC:

61728

AN:

151874

Hom.:

12693

Cov.:

show subpopulations

Gnomad AFR

AF:

0.379

Gnomad AMI

AF:

0.513

Gnomad AMR

AF:

0.316

Gnomad ASJ

AF:

0.376

Gnomad EAS

AF:

0.377

Gnomad SAS

AF:

0.356

Gnomad FIN

AF:

0.502

Gnomad MID

AF:

0.386

Gnomad NFE

AF:

0.436

Gnomad OTH

AF:

0.377

GnomAD3 exomes

AF:

0.400

AC:

99661

AN:

249098

Hom.:

20838

AF XY:

0.404

AC XY:

54456

AN XY:

134780

show subpopulations

Gnomad AFR exome

AF:

0.381

Gnomad AMR exome

AF:

0.261

Gnomad ASJ exome

AF:

0.367

Gnomad EAS exome

AF:

0.392

Gnomad SAS exome

AF:

0.379

Gnomad FIN exome

AF:

0.495

Gnomad NFE exome

AF:

0.437

Gnomad OTH exome

AF:

0.405

GnomAD4 exome

AF:

0.429

AC:

625783

AN:

1460186

Hom.:

135855

Cov.:

AF XY:

0.427

AC XY:

310307

AN XY:

726338

show subpopulations

Gnomad4 AFR exome

AF:

0.374

Gnomad4 AMR exome

AF:

0.267

Gnomad4 ASJ exome

AF:

0.373

Gnomad4 EAS exome

AF:

0.372

Gnomad4 SAS exome

AF:

0.377

Gnomad4 FIN exome

AF:

0.490

Gnomad4 NFE exome

AF:

0.442

Gnomad4 OTH exome

AF:

0.415

GnomAD4 genome

AF:

0.406

AC:

61755

AN:

151992

Hom.:

12699

Cov.:

AF XY:

0.409

AC XY:

30354

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.379

Gnomad4 AMR

AF:

0.316

Gnomad4 ASJ

AF:

0.376

Gnomad4 EAS

AF:

0.376

Gnomad4 SAS

AF:

0.357

Gnomad4 FIN

AF:

0.502

Gnomad4 NFE

AF:

0.436

Gnomad4 OTH

AF:

0.372

Alfa

AF:

0.421

Hom.:

14297

Bravo

AF:

0.389

TwinsUK

AF:

0.444

AC:

1648

ALSPAC

AF:

0.447

AC:

1724

ESP6500AA

AF:

0.373

AC:

1644

ESP6500EA

AF:

0.437

AC:

3754

ExAC

AF:

0.406

AC:

49326

Asia WGS

AF:

0.337

AC:

1171

AN:

3478

EpiCase

AF:

0.421

EpiControl

AF:

0.421

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 29, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 17, 2021	Variant summary: ATP6V1B1 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The variant allele was found at a frequency of 0.4 in 249098 control chromosomes in the gnomAD database, including 20838 homozygotes. The observed variant frequency is approximately 357 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP6V1B1 causing Renal Tubular Acidosis With Progressive Nerve Deafness phenotype (0.0011), strongly suggesting that the variant is benign. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
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. -

not provided

Benign:2

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

Renal tubular acidosis with progressive nerve deafness

Benign:2

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	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;.;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.90

D;D;D

MetaRNN

Benign

0.0050

T;T;T

MetaSVM

Benign

-1.1

PROVEAN

Benign

-0.57

N;N;N

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;.;D

Polyphen

0.83

P;.;P

Vest4

0.57

ClinPred

0.034

GERP RS

4.9

Varity_R

0.89

gMVP

0.60

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