rs17720303

chr2-70936043-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 12/19 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.75

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 -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	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	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.: 32

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

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.: 44 AF XY: 0.172 AC XY: 124795 AN XY: 727116

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.: 32 AF XY: 0.167 AC XY: 12383 AN XY: 74354

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	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. -
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	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, 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0091
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	T;T;T
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.99	L;.;.
MutationTaster	Benign	0.00010	P;P
PrimateAI	Uncertain	0.71	T
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	T
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

Other links and lift over

dbSNP: rs17720303; hg19: chr2-71163173; COSMIC: COSV52265977; COSMIC: COSV52265977;