16-2519686-T-C

Position:

• chr16-2519686-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001694.4(ATP6V0C):​c.409T>C​(p.Phe137Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATP6V0C NM_001694.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.75

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]

ENSG00000260272 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847
• PP5: Variant 16-2519686-T-C is Pathogenic according to our data. Variant chr16-2519686-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2575306.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V0C	NM_001694.4	c.409T>C	p.Phe137Leu	missense_variant	3/3	ENST00000330398.9	NP_001685.1
ATP6V0C	NM_001198569.2	c.409T>C	p.Phe137Leu	missense_variant	4/4		NP_001185498.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V0C	ENST00000330398.9	c.409T>C	p.Phe137Leu	missense_variant	3/3	1	NM_001694.4	ENSP00000329757.4
ENSG00000260272	ENST00000564543.1	c.*164T>C		3_prime_UTR_variant	3/3	2		ENSP00000455547.1
ENSG00000259784	ENST00000569317.1	c.80-1298T>C		intron_variant		3		ENSP00000455561.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459796 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725768

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

EPILEPSY, EARLY-ONSET, 3, WITH DEVELOPMENTAL DELAY Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;.;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.21	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.88
MutPred		0.68		Gain of catalytic residue at F137 (P = 0.1885);.;.;
MVP		0.37
MPC		3.2
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.7
Varity_R		0.94
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr16-2569687;