Genetic Variant C2CD4D:p.Arg217Ser (chr1-151838341-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001394591.1(C2CD4D):c.649C>A(p.Arg217Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000395 in 1,265,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R217C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000040 ( 0 hom. )

Consequence

C2CD4D
NM_001394591.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.342

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.044935107).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394591.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C2CD4D	NM_001394591.1	MANE Select	c.649C>A	p.Arg217Ser	missense	Exon 2 of 2	NP_001381520.1	B7Z1M9
C2CD4D	NM_001136003.2		c.649C>A	p.Arg217Ser	missense	Exon 2 of 2	NP_001129475.1	B7Z1M9
C2CD4D	NM_001394592.1		c.649C>A	p.Arg217Ser	missense	Exon 2 of 2	NP_001381521.1	B7Z1M9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C2CD4D	ENST00000694868.1	MANE Select	c.649C>A	p.Arg217Ser	missense	Exon 2 of 2	ENSP00000511551.1	B7Z1M9
C2CD4D	ENST00000454109.1	TSL:2	c.649C>A	p.Arg217Ser	missense	Exon 2 of 2	ENSP00000389554.1	B7Z1M9
C2CD4D	ENST00000694869.1		c.649C>A	p.Arg217Ser	missense	Exon 2 of 2	ENSP00000511552.1	B7Z1M9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000158

AC:

AN:

63370

AF XY:

0.0000271

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000395

AC:

AN:

1265604

Hom.:

Cov.:

AF XY:

0.00000644

AC XY:

AN XY:

621424

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25098

American (AMR)

AF:

0.00

AC:

AN:

19020

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20744

East Asian (EAS)

AF:

0.00

AC:

AN:

27080

South Asian (SAS)

AF:

0.0000324

AC:

AN:

61704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3958

European-Non Finnish (NFE)

AF:

0.00000197

AC:

AN:

1013186

Other (OTH)

AF:

0.0000195

AC:

AN:

51224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.016

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.41

M_CAP

Benign

0.025

MetaRNN

Benign

0.045

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.9

PhyloP100

0.34

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.9

REVEL

Benign

0.017

Sift

Benign

0.056

Sift4G

Uncertain

0.0080

Polyphen

0.016

Vest4

0.074

MutPred

0.31

Loss of MoRF binding (P = 0.0145)

MVP

0.13

ClinPred

0.22

GERP RS

2.3

Varity_R

0.13

gMVP

0.23

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over