rs2266918

chr2-70943677-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001692.4(ATP6V1B1):c.138C>T(p.Ser46=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,613,456 control chromosomes in the GnomAD database, including 38,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3182 hom., cov: 32)
  • Exomes 𝑓: 0.20 (35805 hom.)
• Consequence: ATP6V1B1 NM_001692.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.39

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-AS1 (HGNC:51118): (ATP6V1B1 antisense RNA 1)

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 2-70943677-C-T is Benign according to our data. Variant chr2-70943677-C-T is described in ClinVar as [Benign]. Clinvar id is 44225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-70943677-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V1B1	NM_001692.4	c.138C>T	p.Ser46=	synonymous_variant	2/14	ENST00000234396.10
ATP6V1B1-AS1	NR_110274.1	n.386-1244G>A		intron_variant, non_coding_transcript_variant
ATP6V1B1-AS1	NR_110273.1	n.524-1244G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V1B1	ENST00000234396.10	c.138C>T	p.Ser46=	synonymous_variant	2/14	1	NM_001692.4	P1
ATP6V1B1-AS1	ENST00000422761.1	n.523-1244G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28653 AN: 151946 Hom.: 3176 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.525

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.185

GnomAD3 exomes AF: 0.240 AC: 60156 AN: 250570 Hom.: 9047 AF XY: 0.248 AC XY: 33603 AN XY: 135462

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.225

Gnomad EAS exome AF: 0.553

Gnomad SAS exome AF: 0.400

Gnomad FIN exome AF: 0.237

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.218

GnomAD4 exome AF: 0.204 AC: 298454 AN: 1461390 Hom.: 35805 Cov.: 34 AF XY: 0.210 AC XY: 152781 AN XY: 726992

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.196

Gnomad4 ASJ exome AF: 0.222

Gnomad4 EAS exome AF: 0.540

Gnomad4 SAS exome AF: 0.395

Gnomad4 FIN exome AF: 0.243

Gnomad4 NFE exome AF: 0.177

Gnomad4 OTH exome AF: 0.220

GnomAD4 genome AF: 0.189 AC: 28670 AN: 152066 Hom.: 3182 Cov.: 32 AF XY: 0.196 AC XY: 14557 AN XY: 74344

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.226

Gnomad4 EAS AF: 0.525

Gnomad4 SAS AF: 0.397

Gnomad4 FIN AF: 0.234

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.186

Alfa AF: 0.177 Hom.: 2365

Bravo AF: 0.175

Asia WGS AF: 0.419 AC: 1459 AN: 3478

EpiCase AF: 0.184

EpiControl AF: 0.180

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ser46Ser in Exon 02 of ATP6V1B1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 17.7% (1240/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2266918). -

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	Genome-Nilou Lab	Jul 10, 2021	- -
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. -

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_noAF	Benign	-0.36
Cadd	Benign	3.8
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2266918; hg19: chr2-71170807; COSMIC: COSV52268446; COSMIC: COSV52268446;