4-5568494-G-A

Variant names:

• chr4-5568494-G-A
• rs12511039
• NM_147127.5:c.3507C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 21 publications found

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]

EVC2 Gene-Disease associations (from GenCC):

• acrofacial dysostosis, Weyers type

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Ellis-van Creveld syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 195539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
EVC2	NM_147127.5	c.3507C>T	p.His1169His	synonymous_variant	Exon 20 of 22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.3507C>T	p.His1169His	synonymous_variant	Exon 20 of 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

GnomAD2 exomes AF: 0.391 AC: 81988 AN: 209712 AF XY: 0.398

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 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

African (AFR) AF: 0.175 AC: 5805 AN: 33264

American (AMR) AF: 0.413 AC: 17212 AN: 41724

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 7701 AN: 25450

East Asian (EAS) AF: 0.875 AC: 34240 AN: 39136

South Asian (SAS) AF: 0.519 AC: 42506 AN: 81858

European-Finnish (FIN) AF: 0.328 AC: 14023 AN: 42818

Middle Eastern (MID) AF: 0.354 AC: 1481 AN: 4188

European-Non Finnish (NFE) AF: 0.300 AC: 331521 AN: 1103528

Other (OTH) AF: 0.341 AC: 20334 AN: 59580

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

African (AFR) AF: 0.177 AC: 7332 AN: 41368

American (AMR) AF: 0.354 AC: 5393 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1078 AN: 3470

East Asian (EAS) AF: 0.863 AC: 4347 AN: 5036

South Asian (SAS) AF: 0.537 AC: 2567 AN: 4784

European-Finnish (FIN) AF: 0.339 AC: 3572 AN: 10532

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20572 AN: 67870

Other (OTH) AF: 0.312 AC: 654 AN: 2098

Alfa AF: 0.307 Hom.: 21445

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

Jun 23, 2014

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

- -

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:2

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. -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.4
DANN	Benign	0.43
PhyloP100		0.59
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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