rs77794859

chr2-70965133-G-Achr2-70965133-G-C

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.*12G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00504 in 1,606,664 control chromosomes in the GnomAD database, including 355 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (173 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (182 hom.)
• Consequence: ATP6V1B1 NM_001692.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.96

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 (BayesDel_noAF=-0.71).
• BP6: Variant 2-70965133-G-A is Benign according to our data. Variant chr2-70965133-G-A is described in ClinVar as [Benign]. Clinvar id is 44220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-70965133-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V1B1	NM_001692.4	c.*12G>A		3_prime_UTR_variant	14/14	ENST00000234396.10
ATP6V1B1	XM_011532907.3	c.*12G>A		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V1B1	ENST00000234396.10	c.*12G>A		3_prime_UTR_variant	14/14	1	NM_001692.4	P1
ATP6V1B1	ENST00000412314.5	c.*12G>A		3_prime_UTR_variant	14/14	5
VAX2	ENST00000432367.6	c.*1330G>A		3_prime_UTR_variant, NMD_transcript_variant	15/15	5
ATP6V1B1	ENST00000433895.2			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0262 AC: 3981 AN: 152094 Hom.: 171 Cov.: 31

Gnomad AFR AF: 0.0920

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00665 AC: 1599 AN: 240542 Hom.: 81 AF XY: 0.00530 AC XY: 700 AN XY: 132074

Gnomad AFR exome AF: 0.0987

Gnomad AMR exome AF: 0.00311

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000182

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.00281 AC: 4091 AN: 1454452 Hom.: 182 Cov.: 33 AF XY: 0.00241 AC XY: 1747 AN XY: 723906

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000917

Gnomad4 OTH exome AF: 0.00601

GnomAD4 genome AF: 0.0263 AC: 4001 AN: 152212 Hom.: 173 Cov.: 31 AF XY: 0.0260 AC XY: 1938 AN XY: 74410

Gnomad4 AFR AF: 0.0922

Gnomad4 AMR AF: 0.00804

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0216 Hom.: 28

Bravo AF: 0.0301

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal tubular acidosis with progressive nerve deafness Benign:2

Benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -
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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

*12G>A in Exon 14 of ATP6V1B1: This variant is not expected to have clinical sig nificance because it has been identified in 8.1% (301/3718) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs77794859). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	3.8
Dann	Benign	0.93

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: rs77794859; hg19: chr2-71192263;