rs2286343

Variant names:

• chr4-5745345-C-T
• rs2286343
• NM_153717.3:c.939+4C>T

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+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,612,486 control chromosomes in the GnomAD database, including 96,525 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9303 hom., cov: 31)
  • Exomes 𝑓: 0.34 (87222 hom.)
• Consequence: EVC NM_153717.3 splice_region, intron
• Scores: Splicing: ADA: 0.01367
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.69
• Publications: 18 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=-0.86).
• BP6: Variant 4-5745345-C-T is Benign according to our data. Variant chr4-5745345-C-T is described in ClinVar as Benign. ClinVar VariationId is 262785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153717.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	NM_153717.3	MANE Select	c.939+4C>T		splice_region intron	N/A	NP_714928.1
	EVC	NM_001306090.2		c.939+4C>T		splice_region intron	N/A	NP_001293019.1
	EVC	NM_001306092.2		c.939+4C>T		splice_region intron	N/A	NP_001293021.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	ENST00000264956.11	TSL:1 MANE Select	c.939+4C>T		splice_region intron	N/A	ENSP00000264956.6
	EVC	ENST00000509451.1	TSL:1	c.939+4C>T		splice_region intron	N/A	ENSP00000426774.1

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51696 AN: 150980 Hom.: 9309 Cov.: 31

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.396

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.650

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.349

GnomAD2 exomes AF: 0.382 AC: 96022 AN: 251298 AF XY: 0.379

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.525

Gnomad ASJ exome AF: 0.311

Gnomad EAS exome AF: 0.649

Gnomad FIN exome AF: 0.332

Gnomad NFE exome AF: 0.319

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.338 AC: 493256 AN: 1461388 Hom.: 87222 Cov.: 43 AF XY: 0.340 AC XY: 246919 AN XY: 726990

African (AFR) AF: 0.289 AC: 9668 AN: 33470

American (AMR) AF: 0.512 AC: 22899 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 8026 AN: 26126

East Asian (EAS) AF: 0.662 AC: 26276 AN: 39684

South Asian (SAS) AF: 0.406 AC: 35056 AN: 86248

European-Finnish (FIN) AF: 0.336 AC: 17922 AN: 53378

Middle Eastern (MID) AF: 0.380 AC: 2187 AN: 5760

European-Non Finnish (NFE) AF: 0.315 AC: 350635 AN: 1111646

Other (OTH) AF: 0.341 AC: 20587 AN: 60376

GnomAD4 genome AF: 0.342 AC: 51725 AN: 151098 Hom.: 9303 Cov.: 31 AF XY: 0.349 AC XY: 25754 AN XY: 73792

African (AFR) AF: 0.293 AC: 11958 AN: 40868

American (AMR) AF: 0.438 AC: 6679 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1068 AN: 3470

East Asian (EAS) AF: 0.651 AC: 3330 AN: 5118

South Asian (SAS) AF: 0.415 AC: 1981 AN: 4772

European-Finnish (FIN) AF: 0.334 AC: 3505 AN: 10480

Middle Eastern (MID) AF: 0.342 AC: 100 AN: 292

European-Non Finnish (NFE) AF: 0.324 AC: 22015 AN: 67856

Other (OTH) AF: 0.349 AC: 730 AN: 2092

Alfa AF: 0.329 Hom.: 16773

Bravo AF: 0.348

Asia WGS AF: 0.508 AC: 1762 AN: 3478

EpiCase AF: 0.329

EpiControl AF: 0.331

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 21, 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 Benign:4

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.

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 15, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.79
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.086
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2286343; hg19: chr4-5747072; COSMIC: COSV53833302; COSMIC: COSV53833302;