Genetic Variant NM_001286577.2:c.6965G>C (chr11-74013482-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001286577.2(C2CD3):c.6965G>C(p.Cys2322Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,413,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

C2CD3
NM_001286577.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.959

Publications

1 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, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

C2CD3 links:

ENSG00000298570 (HGNC:):

ENSG00000298570 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03307107).

BP6

Variant 11-74013482-C-G is Benign according to our data. Variant chr11-74013482-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2053300.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286577.2. 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
	C2CD3	NM_001286577.2	MANE Select	c.6965G>C	p.Cys2322Ser	missense	Exon 33 of 33	NP_001273506.1	Q4AC94-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C2CD3	ENST00000334126.12	TSL:5 MANE Select	c.6965G>C	p.Cys2322Ser	missense	Exon 33 of 33	ENSP00000334379.7	Q4AC94-5
C2CD3	ENST00000679906.1		c.6891G>C	p.Leu2297Phe	missense	Exon 32 of 32	ENSP00000505021.1	A0A7P0T883
C2CD3	ENST00000681143.1		c.6560G>C	p.Cys2187Ser	missense	Exon 30 of 30	ENSP00000505970.1	A0A7P0Z4H1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD2 exomes

AF:

0.000233

AC:

AN:

47182

AF XY:

0.000189

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00190

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:

0.0000111

AC:

AN:

1261510

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

618708

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26248

American (AMR)

AF:

0.000700

AC:

AN:

17140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20188

East Asian (EAS)

AF:

0.00

AC:

AN:

29270

South Asian (SAS)

AF:

0.00

AC:

AN:

59506

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30712

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5198

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1021262

Other (OTH)

AF:

0.0000385

AC:

AN:

51986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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:

0.0000460

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.000458

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.000193

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.025

Eigen

Benign

-0.048

Eigen_PC

Benign

0.014

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.45

M_CAP

Benign

0.0035

MetaRNN

Benign

0.033

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.0

PhyloP100

0.96

PROVEAN

Benign

-0.020

REVEL

Benign

0.024

Sift

Benign

0.60

Sift4G

Benign

0.58

Vest4

0.16

MutPred

0.23

Gain of phosphorylation at C2322 (P = 0.002)

MVP

0.24

ClinPred

0.058

GERP RS

3.6

Varity_R

0.11

gMVP

0.36

Mutation Taster

=96/4

polymorphism

(source)

Splicing

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