chr6-31546134-T-C

Position:

chr6-31546134-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_130463.4(ATP6V1G2):c.158A>G(p.His53Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

ATP6V1G2
NM_130463.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63

Variant links:

Genes affected

ATP6V1G2 (HGNC:862): (ATPase H+ transporting V1 subunit G2) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. V-ATPase dependent 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 three V1 domain G subunit proteins. This gene had previous gene symbols of ATP6G and ATP6G2. Alternatively spliced transcript variants encoding different isoforms have been described. Read-through transcription also exists between this gene and the downstream DEAD (Asp-Glu-Ala-Asp) box polypeptide 39B (DDX39B) gene. [provided by RefSeq, Feb 2011]

ATP6V1G2 links:

ATP6V1G2-DDX39B (HGNC:):

ATP6V1G2-DDX39B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.012223601).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ATP6V1G2	NM_130463.4 linkuse as main transcript	c.158A>G	p.His53Arg	missense_variant	2/3	ENST00000303892.10
ATP6V1G2-DDX39B	NR_037853.1 linkuse as main transcript	n.447A>G		non_coding_transcript_exon_variant	2/13
ATP6V1G2	NM_138282.3 linkuse as main transcript	c.35A>G	p.His12Arg	missense_variant	2/3
ATP6V1G2	NM_001204078.2 linkuse as main transcript	c.105+53A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V1G2	ENST00000303892.10 linkuse as main transcript	c.158A>G	p.His53Arg	missense_variant	2/3	1	NM_130463.4	P1	O95670-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251476

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00120

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00108

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.000140

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

The c.158A>G (p.H53R) alteration is located in exon 2 (coding exon 2) of the ATP6V1G2 gene. This alteration results from a A to G substitution at nucleotide position 158, causing the histidine (H) at amino acid position 53 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.0037

T;.;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.21

.;T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

N;.;.

MutationTaster

Benign

1.0

D;N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

3.0

N;N;N

REVEL

Benign

0.066

Sift

Benign

0.33

T;T;T

Sift4G

Benign

0.41

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.19

MutPred

0.37

Gain of MoRF binding (P = 0.014);.;.;

MVP

0.41

MPC

0.52

ClinPred

0.068

GERP RS

5.5

Varity_R

0.11

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over