rs2286342

Positions:

• chr4-5745351-A-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 262784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5745351-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
EVC	NM_153717.3	c.939+10A>G		intron_variant		ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC	ENST00000264956.11	c.939+10A>G		intron_variant		1	NM_153717.3	P1
EVC	ENST00000509451.1	c.939+10A>G		intron_variant		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

GnomAD3 exomes AF: 0.621 AC: 156079 AN: 251244 Hom.: 49870 AF XY: 0.624 AC XY: 84739 AN XY: 135796

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 SAS exome AF: 0.592

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

Gnomad4 AFR exome AF: 0.713

Gnomad4 AMR exome AF: 0.491

Gnomad4 ASJ exome AF: 0.704

Gnomad4 EAS exome AF: 0.338

Gnomad4 SAS exome AF: 0.594

Gnomad4 FIN exome AF: 0.673

Gnomad4 NFE exome AF: 0.689

Gnomad4 OTH exome AF: 0.663

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

Gnomad4 AFR AF: 0.713

Gnomad4 AMR AF: 0.568

Gnomad4 ASJ AF: 0.704

Gnomad4 EAS AF: 0.351

Gnomad4 SAS AF: 0.590

Gnomad4 FIN AF: 0.680

Gnomad4 NFE AF: 0.680

Gnomad4 OTH AF: 0.656

Alfa AF: 0.688 Hom.: 10447

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2018	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Curry-Hall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.1
DANN	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs2286342; hg19: chr4-5747078; COSMIC: COSV53830462; COSMIC: COSV53830462;