NM_153717.3:c.1026G>C

Variant names:

• chr4-5748234-G-C
• rs4688962
• NM_153717.3:c.1026G>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_153717.3(EVC):​c.1026G>C​(p.Leu342Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,613,678 control chromosomes in the GnomAD database, including 186,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (22249 hom., cov: 32)
  • Exomes 𝑓: 0.47 (164530 hom.)
• Consequence: EVC NM_153717.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.359

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]

CRMP1 (HGNC:2365): (collapsin response mediator protein 1) This gene encodes a member of a family of cytosolic phosphoproteins expressed exclusively in the nervous system. The encoded protein is thought to be a part of the semaphorin signal transduction pathway implicated in semaphorin-induced growth cone collapse during neural development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 4-5748234-G-C is Benign according to our data. Variant chr4-5748234-G-C is described in ClinVar as [Benign]. Clinvar id is 262761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5748234-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.359 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.713 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC	NM_153717.3	c.1026G>C	p.Leu342Leu	synonymous_variant	Exon 8 of 21	ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11	c.1026G>C	p.Leu342Leu	synonymous_variant	Exon 8 of 21	1	NM_153717.3	ENSP00000264956.6
EVC	ENST00000509451.1	c.1026G>C	p.Leu342Leu	synonymous_variant	Exon 8 of 12	1		ENSP00000426774.1
CRMP1	ENST00000506216.5	n.1726C>G		non_coding_transcript_exon_variant	Exon 13 of 13	5

Frequencies

GnomAD3 genomes AF: 0.527 AC: 79947 AN: 151846 Hom.: 22226 Cov.: 32

Gnomad AFR AF: 0.720

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.574

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.510

GnomAD3 exomes AF: 0.483 AC: 121350 AN: 251364 Hom.: 30336 AF XY: 0.485 AC XY: 65923 AN XY: 135832

Gnomad AFR exome AF: 0.725

Gnomad AMR exome AF: 0.384

Gnomad ASJ exome AF: 0.427

Gnomad EAS exome AF: 0.625

Gnomad SAS exome AF: 0.584

Gnomad FIN exome AF: 0.466

Gnomad NFE exome AF: 0.438

Gnomad OTH exome AF: 0.443

GnomAD4 exome AF: 0.470 AC: 686654 AN: 1461714 Hom.: 164530 Cov.: 47 AF XY: 0.473 AC XY: 343664 AN XY: 727152

Gnomad4 AFR exome AF: 0.732

Gnomad4 AMR exome AF: 0.386

Gnomad4 ASJ exome AF: 0.424

Gnomad4 EAS exome AF: 0.642

Gnomad4 SAS exome AF: 0.584

Gnomad4 FIN exome AF: 0.459

Gnomad4 NFE exome AF: 0.451

Gnomad4 OTH exome AF: 0.484

GnomAD4 genome AF: 0.527 AC: 80026 AN: 151964 Hom.: 22249 Cov.: 32 AF XY: 0.529 AC XY: 39291 AN XY: 74266

Gnomad4 AFR AF: 0.720

Gnomad4 AMR AF: 0.415

Gnomad4 ASJ AF: 0.425

Gnomad4 EAS AF: 0.625

Gnomad4 SAS AF: 0.575

Gnomad4 FIN AF: 0.479

Gnomad4 NFE AF: 0.437

Gnomad4 OTH AF: 0.514

Alfa AF: 0.459 Hom.: 5446

Bravo AF: 0.530

Asia WGS AF: 0.598 AC: 2080 AN: 3478

EpiCase AF: 0.438

EpiControl AF: 0.449

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Ellis-van Creveld syndrome Benign:4

Jun 15, 2021

Pars Genome 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

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

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	-0.80
CADD	Benign	7.6
DANN	Benign	0.59

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: rs4688962; hg19: chr4-5749961; COSMIC: COSV53832604; COSMIC: COSV53832604;