rs11681642

chr2-70935956-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.64

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]

ACMG classification

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	UniProt
ATP6V1B1	NM_001692.4	c.2T>C	p.Met1?	start_lost	1/14	ENST00000234396.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V1B1	ENST00000234396.10	c.2T>C	p.Met1?	start_lost	1/14	1	NM_001692.4	P1

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61728 AN: 151874 Hom.: 12693 Cov.: 32

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

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.: 36 AF XY: 0.427 AC XY: 310307 AN XY: 726338

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.: 32 AF XY: 0.409 AC XY: 30354 AN XY: 74272

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 29, 2012	- -
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. -

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	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.90	D;D;D
MetaRNN	Benign	0.0050	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P
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	T
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

Other links and lift over

dbSNP: rs11681642; hg19: chr2-71163086; COSMIC: COSV52265968; COSMIC: COSV52265968;