rs2286342

Variant names:

• chr4-5745351-A-G
• rs2286342
• NM_153717.3:c.939+10A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153717.3(EVC):​c.939+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 1,613,168 control chromosomes in the GnomAD database, including 362,604 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33943 hom., cov: 30)
  • Exomes 𝑓: 0.67 (328661 hom.)
• Consequence: EVC NM_153717.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.191
• Publications: 10 publications found

Genes affected

EVC (HGNC:3497): (EvC ciliary complex subunit 1) This gene encodes a protein containing a leucine zipper and a transmembrane domain. This gene has been implicated in both Ellis-van Creveld syndrome (EvC) and Weyers acrodental dysostosis. [provided by RefSeq, Jul 2008]

EVC Gene-Disease associations (from GenCC):

• acrofacial dysostosis, Weyers type

  Inheritance: AD, Unknown, AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Ellis-van Creveld syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 4-5745351-A-G is Benign according to our data. Variant chr4-5745351-A-G is described in ClinVar as Benign. ClinVar VariationId is 262784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC	NM_153717.3	c.939+10A>G		intron_variant	Intron 7 of 20	ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11	c.939+10A>G		intron_variant	Intron 7 of 20	1	NM_153717.3	ENSP00000264956.6
EVC	ENST00000509451.1	c.939+10A>G		intron_variant	Intron 7 of 11	1		ENSP00000426774.1

Frequencies

GnomAD3 genomes AF: 0.663 AC: 100741 AN: 151844 Hom.: 33920 Cov.: 30

Gnomad AFR AF: 0.713

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.589

Gnomad FIN AF: 0.680

Gnomad MID AF: 0.657

Gnomad NFE AF: 0.680

Gnomad OTH AF: 0.656

GnomAD2 exomes AF: 0.621 AC: 156079 AN: 251244 AF XY: 0.624

Gnomad AFR exome AF: 0.712

Gnomad AMR exome AF: 0.479

Gnomad ASJ exome AF: 0.699

Gnomad EAS exome AF: 0.351

Gnomad FIN exome AF: 0.677

Gnomad NFE exome AF: 0.684

Gnomad OTH exome AF: 0.646

GnomAD4 exome AF: 0.667 AC: 973956 AN: 1461206 Hom.: 328661 Cov.: 41 AF XY: 0.664 AC XY: 482989 AN XY: 726946

African (AFR) AF: 0.713 AC: 23850 AN: 33470

American (AMR) AF: 0.491 AC: 21950 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 18382 AN: 26122

East Asian (EAS) AF: 0.338 AC: 13414 AN: 39680

South Asian (SAS) AF: 0.594 AC: 51252 AN: 86242

European-Finnish (FIN) AF: 0.673 AC: 35911 AN: 53378

Middle Eastern (MID) AF: 0.625 AC: 3603 AN: 5768

European-Non Finnish (NFE) AF: 0.689 AC: 765609 AN: 1111492

Other (OTH) AF: 0.663 AC: 39985 AN: 60352

GnomAD4 genome AF: 0.664 AC: 100830 AN: 151962 Hom.: 33943 Cov.: 30 AF XY: 0.657 AC XY: 48843 AN XY: 74292

African (AFR) AF: 0.713 AC: 29542 AN: 41424

American (AMR) AF: 0.568 AC: 8690 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 2441 AN: 3468

East Asian (EAS) AF: 0.351 AC: 1808 AN: 5152

South Asian (SAS) AF: 0.590 AC: 2832 AN: 4802

European-Finnish (FIN) AF: 0.680 AC: 7175 AN: 10558

Middle Eastern (MID) AF: 0.666 AC: 193 AN: 290

European-Non Finnish (NFE) AF: 0.680 AC: 46213 AN: 67960

Other (OTH) AF: 0.656 AC: 1384 AN: 2110

Alfa AF: 0.688 Hom.: 10643

Bravo AF: 0.656

Asia WGS AF: 0.490 AC: 1708 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ellis-van Creveld syndrome Benign:4

Jun 15, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:3

Mar 02, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Curry-Hall syndrome Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.1
DANN	Benign	0.53
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2286342; hg19: chr4-5747078; COSMIC: COSV53830462; COSMIC: COSV53830462;