rs17853498

Positions:

• chr2-70935981-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001692.4(ATP6V1B1):​c.27T>C​(p.Pro9Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,613,628 control chromosomes in the GnomAD database, including 10,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1258 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8939 hom.)
• Consequence: ATP6V1B1 NM_001692.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.64

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-70935981-T-C is Benign according to our data. Variant chr2-70935981-T-C is described in ClinVar as [Benign]. Clinvar id is 44227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-70935981-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V1B1	NM_001692.4	c.27T>C	p.Pro9Pro	synonymous_variant	1/14	ENST00000234396.10	NP_001683.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V1B1	ENST00000234396.10	c.27T>C	p.Pro9Pro	synonymous_variant	1/14	1	NM_001692.4	ENSP00000234396.4

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18017 AN: 151990 Hom.: 1256 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0781

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0904

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.118 AC: 29531 AN: 250604 Hom.: 2318 AF XY: 0.122 AC XY: 16550 AN XY: 135574

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.0569

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.247

Gnomad SAS exome AF: 0.205

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.0879

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.102 AC: 149113 AN: 1461520 Hom.: 8939 Cov.: 39 AF XY: 0.105 AC XY: 76297 AN XY: 727086

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.0587

Gnomad4 ASJ exome AF: 0.119

Gnomad4 EAS exome AF: 0.198

Gnomad4 SAS exome AF: 0.201

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.0892

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.119 AC: 18030 AN: 152108 Hom.: 1258 Cov.: 32 AF XY: 0.122 AC XY: 9096 AN XY: 74358

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.0780

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.225

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.0904

Gnomad4 OTH AF: 0.112

Alfa AF: 0.0800 Hom.: 282

Bravo AF: 0.114

Asia WGS AF: 0.182 AC: 633 AN: 3478

EpiCase AF: 0.0921

EpiControl AF: 0.0899

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Pro9Pro in Exon 01 of ATP6V1B1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 15.4% (577/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17853498). -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.7
DANN	Benign	0.64

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: rs17853498; hg19: chr2-71163111; COSMIC: COSV52265970; COSMIC: COSV52265970;