Genetic Variant C2CD4B:p.Arg271Pro (chr15-62164173-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001007595.3(C2CD4B):c.812G>C(p.Arg271Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000579 in 1,467,938 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

C2CD4B
NM_001007595.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.511

Variant links:

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]

C2CD4B 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
C2CD4B	NM_001007595.3 link	c.812G>C	p.Arg271Pro	missense_variant	Exon 2 of 2	ENST00000380392.4	NP_001007596.2	A6NLJ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C2CD4B	ENST00000380392.4 link	c.812G>C	p.Arg271Pro	missense_variant	Exon 2 of 2	2	NM_001007595.3	ENSP00000369755.3		A6NLJ0

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000140

AC:

AN:

71328

Hom.:

AF XY:

0.0000242

AC XY:

AN XY:

41400

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:

0.0000360

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000623

AC:

AN:

1315866

Hom.:

Cov.:

AF XY:

0.0000632

AC XY:

AN XY:

648646

show subpopulations

Gnomad4 AFR exome

AF:

0.0000382

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000337

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000303

Gnomad4 NFE exome

AF:

0.0000742

Gnomad4 OTH exome

AF:

0.0000183

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.812G>C (p.R271P) alteration is located in exon 2 (coding exon 1) of the C2CD4B gene. This alteration results from a G to C substitution at nucleotide position 812, causing the arginine (R) at amino acid position 271 to be replaced by a proline (P). 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

0.14

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.037

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.94

MetaRNN

Uncertain

0.47

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.1

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.45

Sift

Benign

0.083

Sift4G

Benign

0.21

Polyphen

0.98

Vest4

0.29

MVP

0.79

MPC

2.3

ClinPred

0.96

GERP RS

3.1

Varity_R

0.74

gMVP

0.69

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