2-10771871-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001039362.2(ATP6V1C2):c.503T>C(p.Ile168Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000484 in 1,614,116 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: ATP6V1C2 NM_001039362.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02

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]

LOC105373428 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-10771871-T-C is Pathogenic according to our data. Variant chr2-10771871-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1344706.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.016740263).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V1C2	NM_001039362.2	c.503T>C	p.Ile168Thr	missense_variant	7/14	ENST00000272238.9
LOC105373428	XR_922797.4	n.963+570A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V1C2	ENST00000272238.9	c.503T>C	p.Ile168Thr	missense_variant	7/14	5	NM_001039362.2
ATP6V1C2	ENST00000635370.1	c.533T>C	p.Ile178Thr	missense_variant	7/14	5
ATP6V1C2	ENST00000381661.3	c.503T>C	p.Ile168Thr	missense_variant	7/13	2		P1
ATP6V1C2	ENST00000648362.1	c.503T>C	p.Ile168Thr	missense_variant	7/12

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 369 AN: 152172 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00854

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000612 AC: 154 AN: 251482 Hom.: 0 AF XY: 0.000434 AC XY: 59 AN XY: 135912

Gnomad AFR exome AF: 0.00794

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000279 AC: 408 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.000246 AC XY: 179 AN XY: 727218

Gnomad4 AFR exome AF: 0.00822

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.00245 AC: 373 AN: 152290 Hom.: 1 Cov.: 33 AF XY: 0.00235 AC XY: 175 AN XY: 74486

Gnomad4 AFR AF: 0.00862

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000362 Hom.: 0

Bravo AF: 0.00277

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000692 AC: 84

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Distal renal tubular acidosis Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Oct 22, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.017	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
Polyphen		1.0	.;D;D;.
Vest4		0.97, 0.93, 0.96
MVP		0.57
MPC		0.81
ClinPred		0.056	T
GERP RS		2.7
Varity_R		0.56
gMVP		0.58

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: rs150980575; hg19: chr2-10911997;