rs121964881

chr2-70958103-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001692.4(ATP6V1B1):c.232G>A(p.Gly78Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G78G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: ATP6V1B1 NM_001692.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.75

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 2-70958103-G-A is Pathogenic according to our data. Variant chr2-70958103-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-70958103-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V1B1	NM_001692.4	c.232G>A	p.Gly78Arg	missense_variant	3/14	ENST00000234396.10
ATP6V1B1	XM_011532907.3	c.352G>A	p.Gly118Arg	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V1B1	ENST00000234396.10	c.232G>A	p.Gly78Arg	missense_variant	3/14	1	NM_001692.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250798 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135580

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727200

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74360

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000324 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 27, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATP6V1B1 function (PMID: 18368028). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP6V1B1 protein function. ClinVar contains an entry for this variant (Variation ID: 12229). This missense change has been observed in individual(s) with ATP6V1B1-related conditions (PMID: 12566520, 23923981, 25498251, 34159584). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121964881, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 78 of the ATP6V1B1 protein (p.Gly78Arg). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2021	Published functional studies demonstrate G78R fails to interact with the E subunit in HEK293 cells (Fuster et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23729491, 9916796, 16769747, 23923981, 16611712, 7499943, 27247958, 28188436, 12566520, 18368028) -

Renal tubular acidosis with progressive nerve deafness Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2003	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 03, 2021	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.7	D;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.96
MutPred		0.95		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.98
gMVP		0.94

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: rs121964881; hg19: chr2-71185233; COSMIC: COSV52269921; COSMIC: COSV52269921;