rs1064793399

Positions:

• chr11-74049471-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001286577.2(C2CD3):​c.5227G>T​(p.Gly1743Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: C2CD3 NM_001286577.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 11-74049471-C-A is Pathogenic according to our data. Variant chr11-74049471-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 418738.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr11-74049471-C-A is described in Lovd as [Pathogenic]. Variant chr11-74049471-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C2CD3	NM_001286577.2	c.5227G>T	p.Gly1743Cys	missense_variant	27/33	ENST00000334126.12
C2CD3	NM_015531.6	c.5227G>T	p.Gly1743Cys	missense_variant	27/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C2CD3	ENST00000334126.12	c.5227G>T	p.Gly1743Cys	missense_variant	27/33	5	NM_001286577.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251364 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135844

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461208 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726940

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 06, 2015

The G1743C substitution in the C2CD3 gene has not been published as a pathogenic variant, nor has it been reported asa benign polymorphism to our knowledge. The G1743C variant was not observed in approximately 6500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The G1743C variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ inpolarity, charge, size and/or other properties. This substitution occurs at a position that is conserved acrossspecies. In silico analysis predicts this variant is probably damaging to the protein structure/function. TheG1743C variant is a strong candidate for a pathogenic variant, however the possibility it may be arare benign variant cannot be excluded. -

Jeune thoracic dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Rare Disease Group, Clinical Genetics, Karolinska Institutet

May 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.2	D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.97
MutPred		0.83		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.74
MPC		0.52
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.87
gMVP		0.64

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

LitVar

Other links and lift over

dbSNP: rs1064793399; hg19: chr11-73760516;