4-5689175-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_147127.5(EVC2):c.688A>G(p.Ser230Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,613,956 control chromosomes in the GnomAD database, including 41,951 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S230R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.22 ( 3753 hom., cov: 33)

Exomes 𝑓: 0.23 ( 38198 hom. )

Consequence

EVC2
NM_147127.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.22

Publications

33 publications found

Variant links:

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

EVC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004810661).

BP6

Variant 4-5689175-T-C is Benign according to our data. Variant chr4-5689175-T-C is described in ClinVar as Benign. ClinVar VariationId is 262620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5 link	c.688A>G	p.Ser230Gly	missense_variant	Exon 5 of 22	ENST00000344408.10	NP_667338.3	Q86UK5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EVC2	ENST00000344408.10 link	c.688A>G	p.Ser230Gly	missense_variant	Exon 5 of 22	1	NM_147127.5	ENSP00000342144.5	Q86UK5-1
EVC2	ENST00000310917.6 link	c.448A>G	p.Ser150Gly	missense_variant	Exon 5 of 22	1		ENSP00000311683.2	Q86UK5-2
EVC2	ENST00000475313.5 link	n.448A>G		non_coding_transcript_exon_variant	Exon 5 of 23	1		ENSP00000431981.1	A0A0C4DGE7
EVC2	ENST00000509670.1 link	n.448A>G		non_coding_transcript_exon_variant	Exon 6 of 23	1		ENSP00000423876.1	E9PFT2

Frequencies

GnomAD3 genomes

AF:

0.221

AC:

33675

AN:

152042

Hom.:

3746

Cov.:

show subpopulations

Gnomad AFR

AF:

0.196

Gnomad AMI

AF:

0.139

Gnomad AMR

AF:

0.238

Gnomad ASJ

AF:

0.231

Gnomad EAS

AF:

0.385

Gnomad SAS

AF:

0.274

Gnomad FIN

AF:

0.229

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.217

Gnomad OTH

AF:

0.236

GnomAD2 exomes

AF:

0.239

AC:

60173

AN:

251426

AF XY:

0.241

show subpopulations

Gnomad AFR exome

AF:

0.196

Gnomad AMR exome

AF:

0.252

Gnomad ASJ exome

AF:

0.220

Gnomad EAS exome

AF:

0.398

Gnomad FIN exome

AF:

0.231

Gnomad NFE exome

AF:

0.214

Gnomad OTH exome

AF:

0.234

GnomAD4 exome

AF:

0.226

AC:

330040

AN:

1461796

Hom.:

38198

Cov.:

AF XY:

0.227

AC XY:

164757

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.188

AC:

6279

AN:

33478

American (AMR)

AF:

0.250

AC:

11188

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

5855

AN:

26132

East Asian (EAS)

AF:

0.347

AC:

13789

AN:

39696

South Asian (SAS)

AF:

0.258

AC:

22212

AN:

86258

European-Finnish (FIN)

AF:

0.227

AC:

12118

AN:

53394

Middle Eastern (MID)

AF:

0.215

AC:

1242

AN:

5768

European-Non Finnish (NFE)

AF:

0.219

AC:

243532

AN:

1111960

Other (OTH)

AF:

0.229

AC:

13825

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

15542

31084

46625

62167

77709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8608

17216

25824

34432

43040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.221

AC:

33693

AN:

152160

Hom.:

3753

Cov.:

AF XY:

0.225

AC XY:

16703

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.196

AC:

8124

AN:

41522

American (AMR)

AF:

0.238

AC:

3640

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.231

AC:

803

AN:

3470

East Asian (EAS)

AF:

0.386

AC:

1992

AN:

5166

South Asian (SAS)

AF:

0.273

AC:

1313

AN:

4818

European-Finnish (FIN)

AF:

0.229

AC:

2421

AN:

10582

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.217

AC:

14725

AN:

67994

Other (OTH)

AF:

0.232

AC:

489

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1396

2791

4187

5582

6978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

372

744

1116

1488

1860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.220

Hom.:

17222

Bravo

AF:

0.222

TwinsUK

AF:

0.224

AC:

831

ALSPAC

AF:

0.226

AC:

871

ESP6500AA

AF:

0.201

AC:

887

ESP6500EA

AF:

0.216

AC:

1856

ExAC

AF:

0.236

AC:

28714

Asia WGS

AF:

0.302

AC:

1047

AN:

3478

EpiCase

AF:

0.221

EpiControl

AF:

0.222

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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. -

Ellis-van Creveld syndrome

Benign:2

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

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.051

T;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.61

T;T

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.

PhyloP100

1.2

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.94

N;N

REVEL

Benign

0.099

Sift

Benign

0.13

T;T

Sift4G

Uncertain

0.025

D;D

Polyphen

0.081

B;.

Vest4

0.042

MPC

0.020

ClinPred

0.0024

GERP RS

1.9

Varity_R

0.067

gMVP

0.47

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over