Genetic Variant C2CD4C:p.Cys345Tyr (chr19-407328-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001136263.2(C2CD4C):c.1034G>A(p.Cys345Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,396,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

C2CD4C
NM_001136263.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.26

Variant links:

Genes affected

C2CD4C (HGNC:29417): (C2 calcium dependent domain containing 4C) Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

C2CD4C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2CD4C	NM_001136263.2 link	c.1034G>A	p.Cys345Tyr	missense_variant	Exon 2 of 2	ENST00000332235.8	NP_001129735.1	Q8TF44
C2CD4C	XM_011527694.2 link	c.1034G>A	p.Cys345Tyr	missense_variant	Exon 2 of 3		XP_011525996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C2CD4C	ENST00000332235.8 link	c.1034G>A	p.Cys345Tyr	missense_variant	Exon 2 of 2	2	NM_001136263.2	ENSP00000328677.4		Q8TF44

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000133

AC:

AN:

149924

Hom.:

AF XY:

0.0000250

AC XY:

AN XY:

80082

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000880

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000107

AC:

AN:

1396780

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

688930

show subpopulations

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:

0.0000252

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000121

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000315

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000418

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1034G>A (p.C345Y) alteration is located in exon 2 (coding exon 1) of the C2CD4C gene. This alteration results from a G to A substitution at nucleotide position 1034, causing the cysteine (C) at amino acid position 345 to be replaced by a tyrosine (Y). 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

Pathogenic

0.62

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.013

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.53

MetaRNN

Uncertain

0.71

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PrimateAI

Pathogenic

0.96

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.32

Sift

Uncertain

0.0060

Sift4G

Benign

0.13

Polyphen

0.15

Vest4

0.79

MutPred

0.65

Loss of stability (P = 0.2665);

MVP

0.32

ClinPred

0.67

GERP RS

3.7

Varity_R

0.80

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over