Genetic Variant NM_001136263.2:c.890G>A (chr19-407472-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001136263.2(C2CD4C):c.890G>A(p.Gly297Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,400,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., 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: 0.291

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 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=0.04661587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2CD4C	NM_001136263.2 link	c.890G>A	p.Gly297Glu	missense_variant	Exon 2 of 2	ENST00000332235.8	NP_001129735.1	Q8TF44
C2CD4C	XM_011527694.2 link	c.890G>A	p.Gly297Glu	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.890G>A	p.Gly297Glu	missense_variant	Exon 2 of 2	2	NM_001136263.2	ENSP00000328677.4		Q8TF44

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000402

AC:

AN:

24878

Hom.:

AF XY:

0.00

AC XY:

AN XY:

12950

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000966

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000112

AC:

AN:

1248312

Hom.:

Cov.:

AF XY:

0.0000132

AC XY:

AN XY:

605416

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000138

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.890G>A (p.G297E) 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 890, causing the glycine (G) at amino acid position 297 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

Benign

0.095

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.026

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.40

M_CAP

Benign

0.018

MetaRNN

Benign

0.047

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.2

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.4

REVEL

Benign

0.016

Sift

Benign

0.66

Sift4G

Benign

0.40

Polyphen

0.0020

Vest4

0.19

MutPred

0.21

Gain of solvent accessibility (P = 0.012);

MVP

0.061

ClinPred

0.018

GERP RS

0.076

Varity_R

0.034

gMVP

0.33

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