rs12511039

Positions:

• chr4-5568494-G-A
• chr4-5568494-G-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.3507C>T​(p.His1169His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,583,144 control chromosomes in the GnomAD database, including 96,128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8194 hom., cov: 30)
  • Exomes 𝑓: 0.33 (87934 hom.)
• Consequence: EVC2 NM_147127.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.586

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=-0.83).
• BP6: Variant 4-5568494-G-A is Benign according to our data. Variant chr4-5568494-G-A is described in ClinVar as [Benign]. Clinvar id is 195539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5568494-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.586 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.842 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC2	NM_147127.5	c.3507C>T	p.His1169His	synonymous_variant	20/22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.3507C>T	p.His1169His	synonymous_variant	20/22	1	NM_147127.5	ENSP00000342144.5

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45734 AN: 151480 Hom.: 8176 Cov.: 30

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.863

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.304

GnomAD3 exomes AF: 0.391 AC: 81988 AN: 209712 Hom.: 18777 AF XY: 0.398 AC XY: 44959 AN XY: 113064

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.421

Gnomad ASJ exome AF: 0.302

Gnomad EAS exome AF: 0.865

Gnomad SAS exome AF: 0.528

Gnomad FIN exome AF: 0.329

Gnomad NFE exome AF: 0.311

Gnomad OTH exome AF: 0.346

GnomAD4 exome AF: 0.332 AC: 474823 AN: 1431546 Hom.: 87934 Cov.: 55 AF XY: 0.338 AC XY: 240155 AN XY: 709972

Gnomad4 AFR exome AF: 0.175

Gnomad4 AMR exome AF: 0.413

Gnomad4 ASJ exome AF: 0.303

Gnomad4 EAS exome AF: 0.875

Gnomad4 SAS exome AF: 0.519

Gnomad4 FIN exome AF: 0.328

Gnomad4 NFE exome AF: 0.300

Gnomad4 OTH exome AF: 0.341

GnomAD4 genome AF: 0.302 AC: 45772 AN: 151598 Hom.: 8194 Cov.: 30 AF XY: 0.313 AC XY: 23171 AN XY: 74044

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.354

Gnomad4 ASJ AF: 0.311

Gnomad4 EAS AF: 0.863

Gnomad4 SAS AF: 0.537

Gnomad4 FIN AF: 0.339

Gnomad4 NFE AF: 0.303

Gnomad4 OTH AF: 0.312

Alfa AF: 0.310 Hom.: 14345

Bravo AF: 0.301

Asia WGS AF: 0.679 AC: 2359 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2014	- -
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. -

Ellis-van Creveld syndrome Benign:2

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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

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	-0.83
CADD	Benign	2.4
DANN	Benign	0.43

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: rs12511039; hg19: chr4-5570221; COSMIC: COSV60387268;