Genetic Variant NM_001394591.1:c.461C>A (chr1-151838529-G-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001394591.1(C2CD4D):c.461C>A(p.Pro154Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000128 in 1,345,236 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 2 hom. )

Consequence

C2CD4D
NM_001394591.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.48

Variant links:

Genes affected

C2CD4D (HGNC:37210): (C2 calcium dependent domain containing 4D)

C2CD4D links:

C2CD4D-AS1 (HGNC:54045): (C2CD4D and THEM5 antisense RNA 1)

C2CD4D-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3302924).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2CD4D	NM_001394591.1 link	c.461C>A	p.Pro154Gln	missense_variant	Exon 2 of 2	ENST00000694868.1	NP_001381520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
C2CD4D	ENST00000694868.1 link	c.461C>A	p.Pro154Gln	missense_variant	Exon 2 of 2		NM_001394591.1	ENSP00000511551.1	B7Z1M9
C2CD4D	ENST00000454109.1 link	c.461C>A	p.Pro154Gln	missense_variant	Exon 2 of 2	2		ENSP00000389554.1	B7Z1M9
C2CD4D	ENST00000694869.1 link	c.461C>A	p.Pro154Gln	missense_variant	Exon 2 of 2			ENSP00000511552.1	B7Z1M9

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151712

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:

0.00116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000139

AC:

166

AN:

1193416

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

579916

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00589

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000508

Gnomad4 OTH exome

AF:

0.0000412

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151820

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74200

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00117

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

Asia WGS

AF:

0.000586

AC:

AN:

3424

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.461C>A (p.P154Q) alteration is located in exon 2 (coding exon 1) of the C2CD4D gene. This alteration results from a C to A substitution at nucleotide position 461, causing the proline (P) at amino acid position 154 to be replaced by a glutamine (Q). 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

0.17

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.38

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.6

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.15

Sift

Benign

0.074

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.17

MutPred

0.18

Gain of MoRF binding (P = 0.0509);

MVP

0.39

ClinPred

0.98

GERP RS

3.5

Varity_R

0.18

gMVP

0.47

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