rs199914263

Variant names:

• chr2-70960926-C-T
• rs199914263
• NM_001692.4:c.591C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001692.4(ATP6V1B1):​c.591C>T​(p.Ala197Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,607,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: ATP6V1B1 NM_001692.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -6.21
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-70960926-C-T is Benign according to our data. Variant chr2-70960926-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 227183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.21 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001692.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1B1	NM_001692.4	MANE Select	c.591C>T	p.Ala197Ala	synonymous	Exon 7 of 14	NP_001683.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1B1	ENST00000234396.10	TSL:1 MANE Select	c.591C>T	p.Ala197Ala	synonymous	Exon 7 of 14	ENSP00000234396.4
	ENSG00000258881	ENST00000606025.5	TSL:5	c.476-18493G>A		intron	N/A	ENSP00000475641.1
	ATP6V1B1	ENST00000412314.5	TSL:5	c.591C>T	p.Ala197Ala	synonymous	Exon 7 of 14	ENSP00000388353.1

Frequencies

GnomAD3 genomes AF: 0.000190 AC: 29 AN: 152242 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000129 AC: 31 AN: 239914 AF XY: 0.000100

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.000536

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000928

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000144 AC: 209 AN: 1455146 Hom.: 0 Cov.: 31 AF XY: 0.000130 AC XY: 94 AN XY: 723168

African (AFR) AF: 0.0000901 AC: 3 AN: 33310

American (AMR) AF: 0.000591 AC: 26 AN: 43962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.0000762 AC: 3 AN: 39362

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84758

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000141 AC: 156 AN: 1108906

Other (OTH) AF: 0.000316 AC: 19 AN: 60138

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152358 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12 AN XY: 74512

African (AFR) AF: 0.000120 AC: 5 AN: 41584

American (AMR) AF: 0.000588 AC: 9 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000181 Hom.: 0

Bravo AF: 0.000193

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Renal tubular acidosis with progressive nerve deafness (2)
-	-	1	ATP6V1B1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.4
DANN	Benign	0.86
PhyloP100		-6.2
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs199914263; hg19: chr2-71188056;