Genetic Variant NM_001286577.2:c.6931G>A (chr11-74013516-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001286577.2(C2CD3):c.6931G>A(p.Glu2311Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,351,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

C2CD3
NM_001286577.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.646

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06894234).

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.6931G>A	p.Glu2311Lys	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.6931G>A	p.Glu2311Lys	missense	Exon 33 of 33	ENSP00000334379.7	Q4AC94-5
C2CD3	ENST00000679906.1		c.6857G>A	p.Arg2286Gln	missense	Exon 32 of 32	ENSP00000505021.1	A0A7P0T883
C2CD3	ENST00000681143.1		c.6526G>A	p.Glu2176Lys	missense	Exon 30 of 30	ENSP00000505970.1	A0A7P0Z4H1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000502

AC:

AN:

19920

AF XY:

0.0000941

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:

0.0000896

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1198940

Hom.:

Cov.:

AF XY:

0.0000172

AC XY:

AN XY:

580726

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

24754

American (AMR)

AF:

0.00

AC:

AN:

11522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17316

East Asian (EAS)

AF:

0.000142

AC:

AN:

28198

South Asian (SAS)

AF:

0.00

AC:

AN:

48658

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4930

European-Non Finnish (NFE)

AF:

0.0000112

AC:

AN:

986110

Other (OTH)

AF:

0.00

AC:

AN:

49170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.000131

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

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:

0.0000264

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

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

0.070

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.022

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.58

M_CAP

Benign

0.0051

MetaRNN

Benign

0.069

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PhyloP100

0.65

PROVEAN

Benign

-0.46

REVEL

Benign

0.0080

Sift

Benign

0.073

Sift4G

Benign

0.53

Vest4

0.046

MutPred

0.19

Gain of ubiquitination at E2311 (P = 0.0048)

MVP

0.18

ClinPred

0.076

GERP RS

2.2

Varity_R

0.035

gMVP

0.32

Mutation Taster

=98/2

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