rs117535770

chr11-74100598-C-T

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.2659G>A(p.Val887Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00557 in 1,614,090 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (41 hom.)
• Consequence: C2CD3 NM_001286577.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.868

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=0.008677304).
• BP6: Variant 11-74100598-C-T is Benign according to our data. Variant chr11-74100598-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 599458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-74100598-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0045 (685/152300) while in subpopulation NFE AF= 0.00687 (467/68024). AF 95% confidence interval is 0.00635. There are 4 homozygotes in gnomad4. There are 326 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C2CD3	NM_001286577.2	c.2659G>A	p.Val887Met	missense_variant	15/33	ENST00000334126.12
C2CD3	NM_015531.6	c.2659G>A	p.Val887Met	missense_variant	15/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C2CD3	ENST00000334126.12	c.2659G>A	p.Val887Met	missense_variant	15/33	5	NM_001286577.2	P2

Frequencies

GnomAD3 genomes AF: 0.00450 AC: 685 AN: 152182 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00829

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00686

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00477 AC: 1198 AN: 251268 Hom.: 6 AF XY: 0.00460 AC XY: 624 AN XY: 135792

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.0100

Gnomad NFE exome AF: 0.00677

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00568 AC: 8308 AN: 1461790 Hom.: 41 Cov.: 31 AF XY: 0.00551 AC XY: 4006 AN XY: 727188

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00273

Gnomad4 ASJ exome AF: 0.00471

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00146

Gnomad4 FIN exome AF: 0.00953

Gnomad4 NFE exome AF: 0.00645

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.00450 AC: 685 AN: 152300 Hom.: 4 Cov.: 32 AF XY: 0.00438 AC XY: 326 AN XY: 74492

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00829

Gnomad4 NFE AF: 0.00687

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00635 Hom.: 11

Bravo AF: 0.00422

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00722 AC: 62

ExAC AF: 0.00474 AC: 576

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00534

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	C2CD3: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 10, 2017

BS1, BS2, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult where full penetrance of the disorder is expected at an early age, and is predicted to be tolerated by multiple functional prediction tools. -

C2CD3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 14, 2022

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

Oct 18, 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	-0.50	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.060	T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.84	T;T
MetaRNN	Benign	0.0087	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	0.74	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.042
Sift	Benign	0.058	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.93	.;P
Vest4		0.39
MVP		0.23
MPC		0.21
ClinPred		0.027	T
GERP RS		4.9
Varity_R		0.086
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs117535770; hg19: chr11-73811643;