chr15-62164227-C-T

Variant names:

• chr15-62164227-C-T
• rs1383992103
• NM_001007595.3:c.758G>A

Variant summary

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

The NM_001007595.3(C2CD4B):​c.758G>A​(p.Arg253His) variant causes a missense change. The variant allele was found at a frequency of 0.00000382 in 1,308,354 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: 0.0000038 (0 hom.)
• Consequence: C2CD4B NM_001007595.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79

Genes affected

C2CD4B (HGNC:33628): (C2 calcium dependent domain containing 4B) Involved in positive regulation of acute inflammatory response; regulation of cell adhesion; and regulation of vascular permeability involved in acute inflammatory response. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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
C2CD4B	NM_001007595.3	c.758G>A	p.Arg253His	missense_variant	Exon 2 of 2	ENST00000380392.4	NP_001007596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C2CD4B	ENST00000380392.4	c.758G>A	p.Arg253His	missense_variant	Exon 2 of 2	2	NM_001007595.3	ENSP00000369755.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000382 AC: 5 AN: 1308354 Hom.: 0 Cov.: 37 AF XY: 0.00000465 AC XY: 3 AN XY: 645094

Gnomad4 AFR exome AF: 0.0000380

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000142

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000191

Gnomad4 OTH exome AF: 0.0000184

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.758G>A (p.R253H) alteration is located in exon 2 (coding exon 1) of the C2CD4B gene. This alteration results from a G to A substitution at nucleotide position 758, causing the arginine (R) at amino acid position 253 to be replaced by a histidine (H). 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	0.096
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.030
Eigen_PC	Benign	-0.0055
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.62
Sift	Benign	0.10	T
Sift4G	Benign	0.18	T
Polyphen		0.88	P
Vest4		0.13
MutPred		0.46		Gain of loop (P = 0.0051);
MVP		0.88
MPC		2.1
ClinPred		0.99	D
GERP RS		1.8
Varity_R		0.20
gMVP		0.15

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

Other links and lift over

dbSNP: rs1383992103; hg19: chr15-62456426;