chr16-2519391-A-T

Position:

• chr16-2519391-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The ENST00000330398.9(ATP6V0C):​c.253A>T​(p.Ser85Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP6V0C ENST00000330398.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

Genes affected

ATP6V0C (HGNC:855): (ATPase H+ transporting V0 subunit c) 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 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. This gene encodes the V0 subunit c. Alternative splicing results in transcript variants. Pseudogenes have been identified on chromosomes 6 and 17. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a chain V-type proton ATPase 16 kDa proteolipid subunit c (size 154) in uniprot entity VATL_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in ENST00000330398.9
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2921258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V0C	NM_001694.4	c.253A>T	p.Ser85Cys	missense_variant	2/3	ENST00000330398.9	NP_001685.1
ATP6V0C	NM_001198569.2	c.253A>T	p.Ser85Cys	missense_variant	3/4		NP_001185498.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V0C	ENST00000330398.9	c.253A>T	p.Ser85Cys	missense_variant	2/3	1	NM_001694.4	ENSP00000329757	P1
ATP6V0C	ENST00000564973.1	c.124A>T	p.Ser42Cys	missense_variant	1/2	2		ENSP00000454868
ATP6V0C	ENST00000565223.1	c.124A>T	p.Ser42Cys	missense_variant	2/3	3		ENSP00000457782
ATP6V0C	ENST00000568562.1	c.*8A>T		3_prime_UTR_variant	2/3	3		ENSP00000454597

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Jul 19, 2022

The c.253A>T (p.S85C) alteration is located in exon 2 (coding exon 2) of the ATP6V0C gene. This alteration results from a A to T substitution at nucleotide position 253, causing the serine (S) at amino acid position 85 to be replaced by a cysteine (C). 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	0.20
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Uncertain	0.75	D;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.88	D;.;D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.0	M;.;.
MutationTaster	Benign	1.0	D;D;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.36	B;.;.
Vest4		0.31
MutPred		0.40		Gain of catalytic residue at L86 (P = 0.0082);.;.;
MVP		0.40
MPC		1.8
ClinPred		0.91	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.45
gMVP		0.97

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: chr16-2569392;