2-10722939-C-A

Position:

• chr2-10722939-C-A

Variant summary

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

The NM_001039362.2(ATP6V1C2):​c.90C>A​(p.Asn30Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00106 in 1,614,064 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: ATP6V1C2 NM_001039362.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.83

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 (HGNC:):

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=0.025514722).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V1C2	NM_001039362.2	c.90C>A	p.Asn30Lys	missense_variant	2/14	ENST00000272238.9	NP_001034451.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V1C2	ENST00000272238.9	c.90C>A	p.Asn30Lys	missense_variant	2/14	5	NM_001039362.2	ENSP00000272238.4
ATP6V1C2	ENST00000635370.1	c.90C>A	p.Asn30Lys	missense_variant	1/14	5		ENSP00000489280.1
ATP6V1C2	ENST00000381661.3	c.90C>A	p.Asn30Lys	missense_variant	2/13	2		ENSP00000371077.3
ATP6V1C2	ENST00000648362.1	c.90C>A	p.Asn30Lys	missense_variant	2/12			ENSP00000497038.1

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152096 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000597 AC: 150 AN: 251428 Hom.: 1 AF XY: 0.000552 AC XY: 75 AN XY: 135882

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.000818

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00110 AC: 1607 AN: 1461850 Hom.: 1 Cov.: 31 AF XY: 0.00104 AC XY: 759 AN XY: 727222

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00120

Gnomad4 NFE exome AF: 0.00127

Gnomad4 OTH exome AF: 0.00127

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152214 Hom.: 0 Cov.: 31 AF XY: 0.000564 AC XY: 42 AN XY: 74426

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.000661

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000593 AC: 72

EpiCase AF: 0.00147

EpiControl AF: 0.00101

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

Dec 17, 2023

The c.90C>A (p.N30K) alteration is located in exon 2 (coding exon 1) of the ATP6V1C2 gene. This alteration results from a C to A substitution at nucleotide position 90, causing the asparagine (N) at amino acid position 30 to be replaced by a lysine (K). 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	0.29
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	.;T;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.026	T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.8	.;L;L;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.1	.;D;D;.
REVEL	Benign	0.17
Sift	Benign	0.091	.;T;T;.
Sift4G	Benign	0.12	.;T;T;T
Polyphen		0.46, 0.93	.;P;P;.
Vest4		0.56, 0.54, 0.56
MutPred		0.66		Loss of ubiquitination at K28 (P = 0.0162);Loss of ubiquitination at K28 (P = 0.0162);Loss of ubiquitination at K28 (P = 0.0162);Loss of ubiquitination at K28 (P = 0.0162);
MVP		0.50
MPC		0.29
ClinPred		0.31	T
GERP RS		4.5
Varity_R		0.47
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs147651089; hg19: chr2-10863065; COSMIC: COSV104378250; COSMIC: COSV104378250;