chr2-70965127-C-A

Variant names:

• chr2-70965127-C-A
• rs45498896
• NM_001692.4:c.*6C>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001692.4(ATP6V1B1):​c.*6C>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 0.0167 in 1,607,700 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (20 hom., cov: 31)
  • Exomes 𝑓: 0.017 (290 hom.)
• Consequence: ATP6V1B1 NM_001692.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0240

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]

ENSG00000258881 (HGNC:):

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=-0.69).
• BP6: Variant 2-70965127-C-A is Benign according to our data. Variant chr2-70965127-C-A is described in ClinVar as [Benign]. Clinvar id is 44221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (2017/152300) while in subpopulation NFE AF= 0.0198 (1344/68022). AF 95% confidence interval is 0.0189. There are 20 homozygotes in gnomad4. There are 973 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V1B1	NM_001692.4	c.*6C>A		3_prime_UTR_variant	Exon 14 of 14	ENST00000234396.10	NP_001683.2
ATP6V1B1	XM_011532907.3	c.*6C>A		3_prime_UTR_variant	Exon 13 of 13		XP_011531209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V1B1	ENST00000234396.10	c.*6C>A		3_prime_UTR_variant	Exon 14 of 14	1	NM_001692.4	ENSP00000234396.4
ENSG00000258881	ENST00000606025.5	c.476-22694G>T		intron_variant	Intron 5 of 5	5		ENSP00000475641.1

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2015 AN: 152182 Hom.: 20 Cov.: 31

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0136 AC: 3278 AN: 241498 Hom.: 40 AF XY: 0.0139 AC XY: 1837 AN XY: 132468

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.00592

Gnomad ASJ exome AF: 0.00645

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00413

Gnomad FIN exome AF: 0.0315

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0171 AC: 24823 AN: 1455400 Hom.: 290 Cov.: 33 AF XY: 0.0168 AC XY: 12175 AN XY: 724340

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.00584

Gnomad4 ASJ exome AF: 0.00605

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00497

Gnomad4 FIN exome AF: 0.0280

Gnomad4 NFE exome AF: 0.0194

Gnomad4 OTH exome AF: 0.0161

GnomAD4 genome AF: 0.0132 AC: 2017 AN: 152300 Hom.: 20 Cov.: 31 AF XY: 0.0131 AC XY: 973 AN XY: 74458

Gnomad4 AFR AF: 0.00325

Gnomad4 AMR AF: 0.00804

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.0297

Gnomad4 NFE AF: 0.0198

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0144 Hom.: 7

Bravo AF: 0.0113

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

*6C>A in Exon 14 of ATP6V1B1: This variant is not expected to have clinical sign ificance because it has been identified in 1.9% (131/6986) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs45498896). -

Aug 14, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Renal tubular acidosis with progressive nerve deafness Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 28, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

Nov 15, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.2
DANN	Benign	0.87

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: rs45498896; hg19: chr2-71192257;