2-10782262-T-C

Position:

chr2-10782262-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_001039362.2(ATP6V1C2):c.1081T>C(p.Phe361Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000272 in 1,614,202 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 2 hom. )

Consequence

ATP6V1C2
NM_001039362.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02

Variant links:

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]

ATP6V1C2 links:

ATP6V1C2 (HGNC:):

ATP6V1C2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.823

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V1C2	NM_001039362.2 linkuse as main transcript	c.1081T>C	p.Phe361Leu	missense_variant	13/14	ENST00000272238.9	NP_001034451.1	Q8NEY4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ATP6V1C2	ENST00000272238.9 linkuse as main transcript	c.1081T>C	p.Phe361Leu	missense_variant	13/14	5	NM_001039362.2	ENSP00000272238.4	Q8NEY4-1
ATP6V1C2	ENST00000635370.1 linkuse as main transcript	c.1111T>C	p.Phe371Leu	missense_variant	13/14	5		ENSP00000489280.1	A0A0U1RR16
ATP6V1C2	ENST00000381661.3 linkuse as main transcript	c.943T>C	p.Phe315Leu	missense_variant	12/13	2		ENSP00000371077.3	Q8NEY4-2
ATP6V1C2	ENST00000480289.1 linkuse as main transcript	n.202T>C		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000183

AC:

AN:

251404

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000318

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:

0.000299

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000281

AC:

411

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

186

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000340

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000184

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000357

Hom.:

Bravo

AF:

0.000272

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

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

Oct 26, 2024

The c.1081T>C (p.F361L) alteration is located in exon 13 (coding exon 12) of the ATP6V1C2 gene. This alteration results from a T to C substitution at nucleotide position 1081, causing the phenylalanine (F) at amino acid position 361 to be replaced by a leucine (L). 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;.;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Uncertain

0.22

MutationAssessor

Pathogenic

3.5

H;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.6

D;D;.

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.78

MutPred

0.95

Loss of helix (P = 0.1299);.;.;

MVP

0.83

MPC

0.78

ClinPred

0.89

GERP RS

5.7

Varity_R

0.88

gMVP

0.75

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