rs140307393

chr11-74085833-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.45

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 Benign. Variant got -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 [Likely_benign]. Clinvar id is 235701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-74085833-T-C is described in Lovd as [Benign]. Variant chr11-74085833-T-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C2CD3	NM_001286577.2	c.3695A>G	p.Asn1232Ser	missense_variant	21/33	ENST00000334126.12
C2CD3	NM_015531.6	c.3695A>G	p.Asn1232Ser	missense_variant	21/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C2CD3	ENST00000334126.12	c.3695A>G	p.Asn1232Ser	missense_variant	21/33	5	NM_001286577.2	P2

Frequencies

GnomAD3 genomes AF: 0.00555 AC: 845 AN: 152116 Hom.: 7 Cov.: 32

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

GnomAD3 exomes AF: 0.00701 AC: 1760 AN: 251072 Hom.: 13 AF XY: 0.00784 AC XY: 1064 AN XY: 135702

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 SAS exome AF: 0.0137

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.: 65 Cov.: 33 AF XY: 0.00835 AC XY: 6073 AN XY: 727224

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00364

Gnomad4 ASJ exome AF: 0.00356

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0136

Gnomad4 FIN exome AF: 0.00215

Gnomad4 NFE exome AF: 0.00869

Gnomad4 OTH exome AF: 0.00782

GnomAD4 genome AF: 0.00555 AC: 845 AN: 152234 Hom.: 7 Cov.: 32 AF XY: 0.00539 AC XY: 401 AN XY: 74418

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00543

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00900

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00782 Hom.: 11

Bravo AF: 0.00548

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00897 AC: 77

ExAC AF: 0.00738 AC: 896

Asia WGS AF: 0.00376 AC: 13 AN: 3476

EpiCase AF: 0.0104

EpiControl AF: 0.00931

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	C2CD3: BS1, BS2 -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

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

-

- -

C2CD3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2019

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	T
BayesDel_noAF	Benign	-0.40
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D
MetaRNN	Benign	0.0087	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
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	T
GERP RS		5.8
Varity_R		0.16
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs140307393; hg19: chr11-73796878;