rs114234874

chr2-70959974-G-A

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.481G>A(p.Glu161Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.025 in 1,614,138 control chromosomes in the GnomAD database, including 794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (65 hom., cov: 32)
  • Exomes 𝑓: 0.025 (729 hom.)
• Consequence: ATP6V1B1 NM_001692.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:12
• Conservation: PhyloP100: 9.99

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=0.0060780346).
• BP6: Variant 2-70959974-G-A is Benign according to our data. Variant chr2-70959974-G-A is described in ClinVar as [Benign]. Clinvar id is 44229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-70959974-G-A is described in Lovd as [Benign]. Variant chr2-70959974-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V1B1	NM_001692.4	c.481G>A	p.Glu161Lys	missense_variant	6/14	ENST00000234396.10
ATP6V1B1	XM_011532907.3	c.601G>A	p.Glu201Lys	missense_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V1B1	ENST00000234396.10	c.481G>A	p.Glu161Lys	missense_variant	6/14	1	NM_001692.4	P1

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 3957 AN: 152156 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.0553

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0635

Gnomad FIN AF: 0.0491

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0339

GnomAD3 exomes AF: 0.0300 AC: 7535 AN: 251352 Hom.: 191 AF XY: 0.0334 AC XY: 4536 AN XY: 135870

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.0586

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0692

Gnomad FIN exome AF: 0.0525

Gnomad NFE exome AF: 0.0230

Gnomad OTH exome AF: 0.0347

GnomAD4 exome AF: 0.0249 AC: 36452 AN: 1461864 Hom.: 729 Cov.: 32 AF XY: 0.0269 AC XY: 19550 AN XY: 727238

Gnomad4 AFR exome AF: 0.0274

Gnomad4 AMR exome AF: 0.0136

Gnomad4 ASJ exome AF: 0.0589

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0712

Gnomad4 FIN exome AF: 0.0528

Gnomad4 NFE exome AF: 0.0201

Gnomad4 OTH exome AF: 0.0284

GnomAD4 genome AF: 0.0260 AC: 3960 AN: 152274 Hom.: 65 Cov.: 32 AF XY: 0.0275 AC XY: 2050 AN XY: 74442

Gnomad4 AFR AF: 0.0261

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.0553

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0644

Gnomad4 FIN AF: 0.0491

Gnomad4 NFE AF: 0.0217

Gnomad4 OTH AF: 0.0331

Alfa AF: 0.0239 Hom.: 71

Bravo AF: 0.0222

TwinsUK AF: 0.0221 AC: 82

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.0259 AC: 114

ESP6500EA AF: 0.0219 AC: 188

ExAC AF: 0.0306 AC: 3714

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal tubular acidosis with progressive nerve deafness Pathogenic:1 Benign:4

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	Counsyl	Mar 06, 2017	- -
Likely pathogenic, flagged submission	clinical testing	Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi	Mar 07, 2022	- -
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 specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 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	Glu161Lys in Exon 06 of ATP6V1B1: This variant is not expected to have clinical significance because it has been identified in 2.4% (90/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs114234874). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 15, 2023	Variant summary: ATP6V1B1 c.481G>A (p.Glu161Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.03 in 251352 control chromosomes in the gnomAD database, including 191 homozygotes. The observed variant frequency is approximately 27-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. To our knowledge, no penetrant association of c.481G>A with Renal Tubular Acidosis With Progressive Nerve Deafness has been reported. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as benign (n=8), and one classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2015	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.;.
Eigen	Benign	0.073
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
MetaRNN	Benign	0.0061	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.47	N;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.9	N;.;N
REVEL	Benign	0.24
Sift	Benign	0.14	T;.;T
Sift4G	Benign	0.20	T;.;T
Polyphen		0.0010	B;.;B
Vest4		0.46
MPC		0.35
ClinPred		0.024	T
GERP RS		4.5
Varity_R		0.28
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.42		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs114234874; hg19: chr2-71187104;