19-407347-C-A

Variant names:

• chr19-407347-C-A
• rs1289061268
• NM_001136263.2:c.1015G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001136263.2(C2CD4C):​c.1015G>T​(p.Ala339Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: C2CD4C NM_001136263.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.421

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13667482).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2CD4C	NM_001136263.2	c.1015G>T	p.Ala339Ser	missense_variant	Exon 2 of 2	ENST00000332235.8	NP_001129735.1
C2CD4C	XM_011527694.2	c.1015G>T	p.Ala339Ser	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	c.1015G>T	p.Ala339Ser	missense_variant	Exon 2 of 2	2	NM_001136263.2	ENSP00000328677.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394568 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 687928

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1015G>T (p.A339S) alteration is located in exon 2 (coding exon 1) of the C2CD4C gene. This alteration results from a G to T substitution at nucleotide position 1015, causing the alanine (A) at amino acid position 339 to be replaced by a serine (S). 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	0.088
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.77	N
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.086
Sift	Benign	0.46	T
Sift4G	Benign	0.17	T
Polyphen		0.065	B
Vest4		0.13
MutPred		0.33		Gain of solvent accessibility (P = 0.3089);
MVP		0.12
ClinPred		0.14	T
GERP RS		2.7
Varity_R		0.046
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs1289061268; hg19: chr19-407347;