rs13131655

Positions:

• chr4-5640547-T-C

Variant summary

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

The NM_147127.5(EVC2):​c.1437A>G​(p.Glu479=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,613,854 control chromosomes in the GnomAD database, including 38,314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6795 hom., cov: 31)
  • Exomes 𝑓: 0.20 (31519 hom.)
• Consequence: EVC2 NM_147127.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.707

Genes affected

EVC2 (HGNC:19747): (EvC ciliary complex subunit 2) This gene encodes a protein that functions in bone formation and skeletal development. Mutations in this gene, as well as in a neighboring gene that lies in a head-to-head configuration, cause Ellis-van Creveld syndrome, an autosomal recessive skeletal dysplasia that is also known as chondroectodermal dysplasia. Mutations in this gene also cause acrofacial dysostosis Weyers type, also referred to as Curry-Hall syndrome, a disease that combines limb and facial abnormalities. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 4-5640547-T-C is Benign according to our data. Variant chr4-5640547-T-C is described in ClinVar as [Benign]. Clinvar id is 193763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.707 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC2	NM_147127.5	c.1437A>G	p.Glu479=	synonymous_variant	10/22	ENST00000344408.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC2	ENST00000344408.10	c.1437A>G	p.Glu479=	synonymous_variant	10/22	1	NM_147127.5	P2
EVC2	ENST00000310917.6	c.1197A>G	p.Glu399=	synonymous_variant	10/22	1		A2
EVC2	ENST00000475313.5	c.1197A>G	p.Glu399=	synonymous_variant, NMD_transcript_variant	10/23	1
EVC2	ENST00000509670.1	c.1197A>G	p.Glu399=	synonymous_variant, NMD_transcript_variant	11/23	1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40787 AN: 151888 Hom.: 6775 Cov.: 31

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.262

GnomAD3 exomes AF: 0.192 AC: 48187 AN: 251396 Hom.: 5941 AF XY: 0.188 AC XY: 25597 AN XY: 135862

Gnomad AFR exome AF: 0.479

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.299

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.150

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.197 AC: 287570 AN: 1461848 Hom.: 31519 Cov.: 37 AF XY: 0.196 AC XY: 142632 AN XY: 727230

Gnomad4 AFR exome AF: 0.493

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.286

Gnomad4 EAS exome AF: 0.000756

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.198

Gnomad4 OTH exome AF: 0.212

GnomAD4 genome AF: 0.269 AC: 40835 AN: 152006 Hom.: 6795 Cov.: 31 AF XY: 0.263 AC XY: 19535 AN XY: 74320

Gnomad4 AFR AF: 0.473

Gnomad4 AMR AF: 0.202

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.166

Gnomad4 NFE AF: 0.206

Gnomad4 OTH AF: 0.259

Alfa AF: 0.233 Hom.: 4158

Bravo AF: 0.279

Asia WGS AF: 0.0980 AC: 342 AN: 3478

EpiCase AF: 0.221

EpiControl AF: 0.221

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 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	Eurofins Ntd Llc (ga)	Jul 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Ellis-van Creveld syndrome Benign:1

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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.5
DANN	Benign	0.67

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: rs13131655; hg19: chr4-5642274; COSMIC: COSV60394164;