rs140307393

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001286577.2(C2CD3):c.3695A>G(p.Asn1232Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00784 in 1,614,070 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0056 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0081 ( 65 hom. )

Consequence

C2CD3
NM_001286577.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.45

Publications

6 publications found

Variant links:

Genes affected

C2CD3 (HGNC:24564): (C2 domain containing 3 centriole elongation regulator) This gene encodes a protein that functions as a regulator of centriole elongation. Studies of the orthologous mouse protein show that it promotes centriolar distal appendage assembly and is also required for the recruitment of other ciliogenic proteins, including intraflagellar transport proteins. Mutations in this gene cause orofaciodigital syndrome XIV (OFD14), a ciliopathy resulting in malformations of the oral cavity, face and digits. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Nov 2014]

C2CD3 Gene-Disease associations (from GenCC):

orofaciodigital syndrome type 14
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

C2CD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 11-74085833-T-C is Benign according to our data. Variant chr11-74085833-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00555 (845/152234) while in subpopulation SAS AF = 0.0112 (54/4824). AF 95% confidence interval is 0.00881. There are 7 homozygotes in GnomAd4. There are 401 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2CD3	NM_001286577.2 link	c.3695A>G	p.Asn1232Ser	missense_variant	Exon 21 of 33	ENST00000334126.12	NP_001273506.1
C2CD3	NM_015531.6 link	c.3695A>G	p.Asn1232Ser	missense_variant	Exon 21 of 31		NP_056346.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C2CD3	ENST00000334126.12 link	c.3695A>G	p.Asn1232Ser	missense_variant	Exon 21 of 33	5	NM_001286577.2	ENSP00000334379.7

Frequencies

GnomAD3 genomes

AF:

0.00555

AC:

845

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00531

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0118

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00898

Gnomad OTH

AF:

0.00384

GnomAD2 exomes

AF:

0.00701

AC:

1760

AN:

251072

AF XY:

0.00784

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00359

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00181

Gnomad NFE exome

AF:

0.00953

Gnomad OTH exome

AF:

0.00752

GnomAD4 exome

AF:

0.00807

AC:

11804

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00835

AC XY:

6073

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

33480

American (AMR)

AF:

0.00364

AC:

163

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00356

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39682

South Asian (SAS)

AF:

0.0136

AC:

1175

AN:

86252

European-Finnish (FIN)

AF:

0.00215

AC:

115

AN:

53412

Middle Eastern (MID)

AF:

0.0133

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00869

AC:

9665

AN:

1111990

Other (OTH)

AF:

0.00782

AC:

472

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

670

1340

2011

2681

3351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

352

704

1056

1408

1760

<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:

0.00555

AC:

845

AN:

152234

Hom.:

Cov.:

AF XY:

0.00539

AC XY:

401

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

41556

American (AMR)

AF:

0.00543

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.0112

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00900

AC:

612

AN:

68004

Other (OTH)

AF:

0.00380

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00748

Hom.:

Bravo

AF:

0.00548

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00897

AC:

ExAC

AF:

0.00738

AC:

896

Asia WGS

AF:

0.00376

AC:

AN:

3476

EpiCase

AF:

0.0104

EpiControl

AF:

0.00931

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 09, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

C2CD3: BS1, BS2 -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

C2CD3-related disorder

Benign:1

Jun 10, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;.;T

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D;D

MetaRNN

Benign

0.0087

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M;.

PhyloP100

7.5

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Benign

0.26

Sift

Benign

0.065

T;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.62

MVP

0.73

MPC

0.45

ClinPred

0.0085

GERP RS

5.8

Varity_R

0.16

gMVP

0.67

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.30

Position offset: 5

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over