rs149910292

Positions:

• chr11-74139608-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001286577.2(C2CD3):​c.704C>T​(p.Pro235Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,604,348 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P235P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (26 hom.)
• Consequence: C2CD3 NM_001286577.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.59

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063070953).
• BP6: Variant 11-74139608-G-A is Benign according to our data. Variant chr11-74139608-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 599461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-74139608-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00361 (549/152254) while in subpopulation NFE AF= 0.0064 (435/68000). AF 95% confidence interval is 0.0059. There are 3 homozygotes in gnomad4. There are 233 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C2CD3	NM_001286577.2	c.704C>T	p.Pro235Leu	missense_variant	4/33	ENST00000334126.12
C2CD3	NM_015531.6	c.704C>T	p.Pro235Leu	missense_variant	4/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C2CD3	ENST00000334126.12	c.704C>T	p.Pro235Leu	missense_variant	4/33	5	NM_001286577.2	P2

Frequencies

GnomAD3 genomes AF: 0.00362 AC: 550 AN: 152136 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00640

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00364 AC: 915 AN: 251392 Hom.: 1 AF XY: 0.00343 AC XY: 466 AN XY: 135876

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00677

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00577 AC: 8374 AN: 1452094 Hom.: 26 Cov.: 30 AF XY: 0.00542 AC XY: 3921 AN XY: 723086

Gnomad4 AFR exome AF: 0.000692

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.000806

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000372

Gnomad4 FIN exome AF: 0.00266

Gnomad4 NFE exome AF: 0.00715

Gnomad4 OTH exome AF: 0.00346

GnomAD4 genome AF: 0.00361 AC: 549 AN: 152254 Hom.: 3 Cov.: 32 AF XY: 0.00313 AC XY: 233 AN XY: 74442

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.00640

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00589 Hom.: 11

Bravo AF: 0.00324

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00710 AC: 61

ExAC AF: 0.00352 AC: 427

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00611

EpiControl AF: 0.00557

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	C2CD3: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Orofaciodigital syndrome type 14 Benign:2

Benign, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Nov 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 08, 2018	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

May 16, 2017

BS1, BS2; This alteration has an allele frequency that is greater than expected for the associated disease, and was seen in a healthy adult where full penetrance of the disorder is expected at an early age. -

C2CD3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Benign	0.82
DEOGEN2	Benign	0.18	T;.;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.0063	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Benign	0.058
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.51	T;T;T
Polyphen		0.0090	B;B;.
Vest4		0.24
MVP		0.10
MPC		0.14
ClinPred		0.015	T
GERP RS		1.8
Varity_R		0.055
gMVP		0.47

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: rs149910292; hg19: chr11-73850653; COSMIC: COSV99043194; COSMIC: COSV99043194;