Genetic Variant C2CD4D:p.Pro251Ser (chr1-151838239-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001394591.1(C2CD4D):c.751C>T(p.Pro251Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,376,928 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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. P251A) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000017 ( 1 hom. )

Consequence

C2CD4D
NM_001394591.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.468

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.062873274).

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.751C>T	p.Pro251Ser	missense	Exon 2 of 2	NP_001381520.1	B7Z1M9
C2CD4D	NM_001136003.2		c.751C>T	p.Pro251Ser	missense	Exon 2 of 2	NP_001129475.1	B7Z1M9
C2CD4D	NM_001394592.1		c.751C>T	p.Pro251Ser	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.751C>T	p.Pro251Ser	missense	Exon 2 of 2	ENSP00000511551.1	B7Z1M9
C2CD4D	ENST00000454109.1	TSL:2	c.751C>T	p.Pro251Ser	missense	Exon 2 of 2	ENSP00000389554.1	B7Z1M9
C2CD4D	ENST00000694869.1		c.751C>T	p.Pro251Ser	missense	Exon 2 of 2	ENSP00000511552.1	B7Z1M9

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151670

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:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000108

AC:

AN:

27756

AF XY:

0.000188

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:

0.0000171

AC:

AN:

1225150

Hom.:

Cov.:

AF XY:

0.0000251

AC XY:

AN XY:

597316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23846

American (AMR)

AF:

0.00

AC:

AN:

10654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16728

East Asian (EAS)

AF:

0.00

AC:

AN:

27926

South Asian (SAS)

AF:

0.000393

AC:

AN:

48304

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42384

Middle Eastern (MID)

AF:

0.000203

AC:

AN:

4928

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1000568

Other (OTH)

AF:

0.0000201

AC:

AN:

49812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.549

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

AF:

0.0000198

AC:

AN:

151778

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74186

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41500

American (AMR)

AF:

0.00

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10424

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67838

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.000172

AC:

Asia WGS

AF:

0.000291

AC:

AN:

3448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.51

M_CAP

Benign

0.025

MetaRNN

Benign

0.063

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PhyloP100

0.47

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.3

REVEL

Benign

0.055

Sift

Benign

0.038

Sift4G

Benign

0.091

Polyphen

0.83

Vest4

0.13

MVP

0.17

ClinPred

0.97

GERP RS

2.4

Varity_R

0.052

gMVP

0.17

Mutation Taster

=88/12

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over