6-31545509-T-A

Position:

• chr6-31545509-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_130463.4(ATP6V1G2):​c.256A>T​(p.Ser86Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP6V1G2 NM_130463.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43

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-DDX39B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34645683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V1G2	NM_130463.4	c.256A>T	p.Ser86Cys	missense_variant	3/3	ENST00000303892.10	NP_569730.1
ATP6V1G2-DDX39B	NR_037853.1	n.472+600A>T		intron_variant, non_coding_transcript_variant
ATP6V1G2	NM_001204078.2	c.136A>T	p.Ser46Cys	missense_variant	3/3		NP_001191007.1
ATP6V1G2	NM_138282.3	c.133A>T	p.Ser45Cys	missense_variant	3/3		NP_612139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V1G2	ENST00000303892.10	c.256A>T	p.Ser86Cys	missense_variant	3/3	1	NM_130463.4	ENSP00000302194	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The c.256A>T (p.S86C) alteration is located in exon 3 (coding exon 3) of the ATP6V1G2 gene. This alteration results from a A to T substitution at nucleotide position 256, causing the serine (S) at amino acid position 86 to be replaced by a cysteine (C). 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	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;T;.;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.77	.;.;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.2	.;M;.;.
MutationTaster	Benign	1.0	D;N;N;N;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.012	D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D
Polyphen		0.97	.;D;.;.
Vest4		0.37
MutPred		0.40		.;Gain of catalytic residue at S86 (P = 0.0714);.;.;
MVP		0.63
MPC		1.2
ClinPred		0.94	D
GERP RS		4.6
Varity_R		0.12
gMVP		0.29

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: rs374873236; hg19: chr6-31513286;