rs73063795

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_147127.5(EVC2):c.1384A>G(p.Thr462Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,614,130 control chromosomes in the GnomAD database, including 53 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T462T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.011 ( 27 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 26 hom. )

Consequence

EVC2
NM_147127.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.552

Publications

6 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=0.0046666563).

BP6

Variant 4-5640600-T-C is Benign according to our data. Variant chr4-5640600-T-C is described in ClinVar as Benign. ClinVar VariationId is 235428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0115 (1745/152244) while in subpopulation AFR AF = 0.0332 (1377/41530). AF 95% confidence interval is 0.0317. There are 27 homozygotes in GnomAd4. There are 845 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 27 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5 link	c.1384A>G	p.Thr462Ala	missense_variant	Exon 10 of 22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
EVC2	ENST00000344408.10 link	c.1384A>G	p.Thr462Ala	missense_variant	Exon 10 of 22	1	NM_147127.5	ENSP00000342144.5
EVC2	ENST00000310917.6 link	c.1144A>G	p.Thr382Ala	missense_variant	Exon 10 of 22	1		ENSP00000311683.2
EVC2	ENST00000475313.5 link	n.1144A>G		non_coding_transcript_exon_variant	Exon 10 of 23	1		ENSP00000431981.1
EVC2	ENST00000509670.1 link	n.1144A>G		non_coding_transcript_exon_variant	Exon 11 of 23	1		ENSP00000423876.1

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1727

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0328

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0158

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.00433

AC:

1089

AN:

251470

AF XY:

0.00361

show subpopulations

Gnomad AFR exome

AF:

0.0330

Gnomad AMR exome

AF:

0.00804

Gnomad ASJ exome

AF:

0.00704

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00141

Gnomad OTH exome

AF:

0.00652

GnomAD4 exome

AF:

0.00212

AC:

3096

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

1447

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0340

AC:

1138

AN:

33480

American (AMR)

AF:

0.00827

AC:

370

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00658

AC:

172

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000128

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00988

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000933

AC:

1037

AN:

1112010

Other (OTH)

AF:

0.00512

AC:

309

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

194

388

583

777

971

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.0115

AC:

1745

AN:

152244

Hom.:

Cov.:

AF XY:

0.0113

AC XY:

845

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0332

AC:

1377

AN:

41530

American (AMR)

AF:

0.0158

AC:

241

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00116

AC:

AN:

68030

Other (OTH)

AF:

0.0133

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

148

222

296

370

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00844

Hom.:

Bravo

AF:

0.0130

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0329

AC:

145

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00435

AC:

528

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00202

EpiControl

AF:

0.00172

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 04, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 06, 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;C0457013:Curry-Hall syndrome

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ellis-van Creveld syndrome

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.0

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.49

T;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.48

T;T

MetaRNN

Benign

0.0047

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

2.0

M;.

PhyloP100

0.55

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.25

Sift

Benign

0.062

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.45

P;.

Vest4

0.085

MVP

0.68

MPC

0.020

ClinPred

0.011

GERP RS

-4.3

Varity_R

0.057

gMVP

0.28

Mutation Taster

=97/3

polymorphism

(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