Genetic Variant NM_001136263.2:c.925G>C (chr19-407437-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001136263.2(C2CD4C):c.925G>C(p.Val309Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000765 in 1,491,158 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000075 ( 2 hom. )

Consequence

C2CD4C
NM_001136263.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.678

Publications

0 publications found

Variant links:

Genes affected

C2CD4C (HGNC:29417): (C2 calcium dependent domain containing 4C) Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

C2CD4C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039624304).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136263.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2CD4C	NM_001136263.2	MANE Select	c.925G>C	p.Val309Leu	missense	Exon 2 of 2	NP_001129735.1	Q8TF44

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2CD4C	ENST00000332235.8	TSL:2 MANE Select	c.925G>C	p.Val309Leu	missense	Exon 2 of 2	ENSP00000328677.4	Q8TF44
	C2CD4C	ENST00000920287.1		c.925G>C	p.Val309Leu	missense	Exon 2 of 2	ENSP00000590346.1

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000995

AC:

AN:

90432

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.000375

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:

0.0000754

AC:

101

AN:

1339064

Hom.:

Cov.:

AF XY:

0.0000913

AC XY:

AN XY:

657266

show subpopulations

African (AFR)

AF:

0.000101

AC:

AN:

29788

American (AMR)

AF:

0.00

AC:

AN:

28818

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21836

East Asian (EAS)

AF:

0.00

AC:

AN:

34910

South Asian (SAS)

AF:

0.000736

AC:

AN:

70660

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33962

Middle Eastern (MID)

AF:

0.000437

AC:

AN:

4576

European-Non Finnish (NFE)

AF:

0.0000331

AC:

AN:

1058802

Other (OTH)

AF:

0.000162

AC:

AN:

55712

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.0000855

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41528

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000736

AC:

AN:

67928

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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.:

Bravo

AF:

0.0000718

ExAC

AF:

0.000535

AC:

Asia WGS

AF:

0.000580

AC:

AN:

3460

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.45

CADD

Benign

6.7

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.0096

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.65

M_CAP

Pathogenic

0.79

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-1.2

PhyloP100

-0.68

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

1.4

REVEL

Benign

0.16

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.19

MutPred

0.48

Loss of MoRF binding (P = 0.0891)

MVP

0.055

ClinPred

0.0028

GERP RS

0.67

Varity_R

0.036

gMVP

0.34

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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