rs587777654

Variant names:

• chr11-74095303-A-C
• rs587777654
• NM_001286577.2:c.3085T>G

Your query was ambiguous. Multiple possible variants found:

• chr11-74095303-A-C
• chr11-74095303-A-G
• chr11-74095303-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001286577.2(C2CD3):​c.3085T>G​(p.Cys1029Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C2CD3 NM_001286577.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.08
• Publications: 4 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 11-74095303-A-C is Pathogenic according to our data. Variant chr11-74095303-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 144039.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2CD3	NM_001286577.2	c.3085T>G	p.Cys1029Gly	missense_variant	Exon 17 of 33	ENST00000334126.12	NP_001273506.1
C2CD3	NM_015531.6	c.3085T>G	p.Cys1029Gly	missense_variant	Exon 17 of 31		NP_056346.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C2CD3	ENST00000334126.12	c.3085T>G	p.Cys1029Gly	missense_variant	Exon 17 of 33	5	NM_001286577.2	ENSP00000334379.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Orofaciodigital syndrome type 14 Pathogenic:1

Aug 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.7	M;M
PhyloP100		9.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-9.2	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.97
MutPred		0.77		Loss of stability (P = 0.0298);Loss of stability (P = 0.0298);
MVP		0.69
MPC		0.56
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.94
gMVP		0.82
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777654; hg19: chr11-73806348;