rs78140305

Positions:

• chr2-70964551-A-G

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.1248+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00507 in 1,613,652 control chromosomes in the GnomAD database, including 359 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (175 hom., cov: 30)
  • Exomes 𝑓: 0.0028 (184 hom.)
• Consequence: ATP6V1B1 NM_001692.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.42

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=-0.89).
• BP6: Variant 2-70964551-A-G is Benign according to our data. Variant chr2-70964551-A-G is described in ClinVar as [Benign]. Clinvar id is 44223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-70964551-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.091 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V1B1	NM_001692.4	c.1248+9A>G		intron_variant		ENST00000234396.10	NP_001683.2
ATP6V1B1	XM_011532907.3	c.1368+9A>G		intron_variant			XP_011531209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V1B1	ENST00000234396.10	c.1248+9A>G		intron_variant		1	NM_001692.4	ENSP00000234396	P1
ATP6V1B1	ENST00000412314.5	c.1197+9A>G		intron_variant		5		ENSP00000388353
ATP6V1B1	ENST00000433895.2	c.180+9A>G		intron_variant		3		ENSP00000407840
VAX2	ENST00000432367.6	c.*1024+9A>G		intron_variant, NMD_transcript_variant		5		ENSP00000405114

Frequencies

GnomAD3 genomes AF: 0.0265 AC: 4029 AN: 152048 Hom.: 172 Cov.: 30

Gnomad AFR AF: 0.0932

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: 0.000162

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00690 AC: 1735 AN: 251406 Hom.: 86 AF XY: 0.00522 AC XY: 709 AN XY: 135898

Gnomad AFR exome AF: 0.0975

Gnomad AMR exome AF: 0.00312

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00283 AC: 4131 AN: 1461486 Hom.: 184 Cov.: 32 AF XY: 0.00242 AC XY: 1761 AN XY: 727086

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.00358

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: 0.0000927

Gnomad4 OTH exome AF: 0.00618

GnomAD4 genome AF: 0.0266 AC: 4050 AN: 152166 Hom.: 175 Cov.: 30 AF XY: 0.0264 AC XY: 1964 AN XY: 74388

Gnomad4 AFR AF: 0.0934

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: 0.000162

Gnomad4 OTH AF: 0.0176

Alfa AF: 0.0141 Hom.: 37

Bravo AF: 0.0304

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal tubular acidosis with progressive nerve deafness Benign:3

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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2018	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	1248+9A>G in Intron 12 of ATP6V1B1: This variant is not expected to have clinica l significance because it is not located within the conserved splice consensus s equence and has been identified in 8.7% (327/3738) of African American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs78140305). -

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	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.6
DANN	Benign	0.81

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: rs78140305; hg19: chr2-71191681;