2-10775019-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001039362.2(ATP6V1C2):c.773A>T(p.Glu258Val) variant causes a missense change. The variant allele was found at a frequency of 0.000132 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: ATP6V1C2 NM_001039362.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25

Genes affected

ATP6V1C2 (HGNC:18264): (ATPase H+ transporting V1 subunit C2) 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,three B, and two G subunits, as well as a C, D, E, F, and H subunit. The V1 domain contains the ATP catalytic site. This gene encodes alternate transcriptional splice variants, encoding different V1 domain C subunit isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

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=0.037667483).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V1C2	NM_001039362.2	c.773A>T	p.Glu258Val	missense_variant	10/14	ENST00000272238.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V1C2	ENST00000272238.9	c.773A>T	p.Glu258Val	missense_variant	10/14	5	NM_001039362.2
ATP6V1C2	ENST00000635370.1	c.803A>T	p.Glu268Val	missense_variant	10/14	5
ATP6V1C2	ENST00000381661.3	c.773A>T	p.Glu258Val	missense_variant	10/13	2		P1
ATP6V1C2	ENST00000648362.1	c.773A>T	p.Glu258Val	missense_variant	10/12

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000123 AC: 31 AN: 251460 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000138 AC: 201 AN: 1461810 Hom.: 0 Cov.: 32 AF XY: 0.000131 AC XY: 95 AN XY: 727204

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74484

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000264 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000382

EpiControl AF: 0.000119

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

Jun 10, 2022

The c.773A>T (p.E258V) alteration is located in exon 10 (coding exon 9) of the ATP6V1C2 gene. This alteration results from a A to T substitution at nucleotide position 773, causing the glutamic acid (E) at amino acid position 258 to be replaced by a valine (V). 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	0.12
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.48	T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.038	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.76	N;N
PrimateAI	Benign	0.37	T
Polyphen		0.0080, 0.0020	.;B;B;.
Vest4		0.33, 0.36, 0.37
MVP		0.41
MPC		0.21
ClinPred		0.079	T
GERP RS		3.3
Varity_R		0.15
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs149903295; hg19: chr2-10915145;