8-103064769-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001695.5(ATP6V1C1):​c.884T>C​(p.Ile295Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

ATP6V1C1
NM_001695.5 missense

Scores

2
13
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.05
Variant links:
Genes affected
ATP6V1C1 (HGNC:856): (ATPase H+ transporting V1 subunit C1) 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 gene is one of two genes that encode the V1 domain C subunit proteins and is found ubiquitously. This C subunit is analogous but not homologous to gamma subunit of F-ATPases. Previously, this gene was designated ATP6D. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP6V1C1NM_001695.5 linkc.884T>C p.Ile295Thr missense_variant Exon 11 of 13 ENST00000518738.2 NP_001686.1 P21283A0A024R9I0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP6V1C1ENST00000518738.2 linkc.884T>C p.Ile295Thr missense_variant Exon 11 of 13 1 NM_001695.5 ENSP00000430282.1 P21283

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 14, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.884T>C (p.I295T) alteration is located in exon 11 (coding exon 10) of the ATP6V1C1 gene. This alteration results from a T to C substitution at nucleotide position 884, causing the isoleucine (I) at amino acid position 295 to be replaced by a threonine (T). 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
Uncertain
0.55
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.070
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.091
T;T;T;T
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.96
.;.;D;D
M_CAP
Benign
0.035
D
MetaRNN
Uncertain
0.72
D;D;D;D
MetaSVM
Benign
-0.33
T
MutationAssessor
Uncertain
2.5
.;M;.;M
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-4.5
D;D;D;D
REVEL
Uncertain
0.34
Sift
Uncertain
0.0020
D;D;D;D
Sift4G
Uncertain
0.013
D;D;D;D
Polyphen
0.85
.;P;.;P
Vest4
0.70
MutPred
0.71
.;Loss of stability (P = 0.0238);.;Loss of stability (P = 0.0238);
MVP
0.76
MPC
0.72
ClinPred
0.99
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.72
gMVP
0.76

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.

Other links and lift over

dbSNP: rs1817460270; hg19: chr8-104076997; API