2-10764368-C-G

Position:

• chr2-10764368-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001039362.2(ATP6V1C2):​c.321C>G​(p.Asp107Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP6V1C2 NM_001039362.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.59

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V1C2	NM_001039362.2	c.321C>G	p.Asp107Glu	missense_variant	5/14	ENST00000272238.9	NP_001034451.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V1C2	ENST00000272238.9	c.321C>G	p.Asp107Glu	missense_variant	5/14	5	NM_001039362.2	ENSP00000272238
ATP6V1C2	ENST00000635370.1	c.351C>G	p.Asp117Glu	missense_variant	5/14	5		ENSP00000489280
ATP6V1C2	ENST00000381661.3	c.321C>G	p.Asp107Glu	missense_variant	5/13	2		ENSP00000371077	P1
ATP6V1C2	ENST00000648362.1	c.321C>G	p.Asp107Glu	missense_variant	5/12			ENSP00000497038

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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 02, 2023

The c.321C>G (p.D107E) alteration is located in exon 5 (coding exon 4) of the ATP6V1C2 gene. This alteration results from a C to G substitution at nucleotide position 321, causing the aspartic acid (D) at amino acid position 107 to be replaced by a glutamic acid (E). 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	0.51
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	.;T;.;.
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.2	.;M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.4	.;D;D;.
REVEL	Uncertain	0.29
Sift	Benign	0.075	.;T;T;.
Sift4G	Benign	0.077	.;T;T;T
Polyphen		0.96, 0.91	.;D;P;.
Vest4		0.86, 0.85, 0.86
MutPred		0.83		Gain of ubiquitination at K110 (P = 0.0585);Gain of ubiquitination at K110 (P = 0.0585);Gain of ubiquitination at K110 (P = 0.0585);.;
MVP		0.62
MPC		0.66
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.52
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-10904494;