rs141287105

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_147127.5(EVC2):c.1364C>G(p.Thr455Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00572 in 1,614,032 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0040 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0059 ( 28 hom. )

Consequence

EVC2
NM_147127.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 4.61

Publications

12 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009402782).

BP6

Variant 4-5640620-G-C is Benign according to our data. Variant chr4-5640620-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193762.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00396 (602/152158) while in subpopulation NFE AF = 0.00723 (492/68022). AF 95% confidence interval is 0.0067. There are 1 homozygotes in GnomAd4. There are 275 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 28 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5 link	c.1364C>G	p.Thr455Arg	missense_variant	Exon 10 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.1364C>G	p.Thr455Arg	missense_variant	Exon 10 of 22	1	NM_147127.5	ENSP00000342144.5	Q86UK5-1
EVC2	ENST00000310917.6 link	c.1124C>G	p.Thr375Arg	missense_variant	Exon 10 of 22	1		ENSP00000311683.2	Q86UK5-2
EVC2	ENST00000475313.5 link	n.1124C>G		non_coding_transcript_exon_variant	Exon 10 of 23	1		ENSP00000431981.1	A0A0C4DGE7
EVC2	ENST00000509670.1 link	n.1124C>G		non_coding_transcript_exon_variant	Exon 11 of 23	1		ENSP00000423876.1	E9PFT2

Frequencies

GnomAD3 genomes

AF:

0.00396

AC:

602

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000870

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000417

Gnomad FIN

AF:

0.00387

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00723

Gnomad OTH

AF:

0.00384

GnomAD2 exomes

AF:

0.00367

AC:

923

AN:

251464

AF XY:

0.00373

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00356

Gnomad NFE exome

AF:

0.00645

Gnomad OTH exome

AF:

0.00603

GnomAD4 exome

AF:

0.00590

AC:

8627

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00575

AC XY:

4179

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33480

American (AMR)

AF:

0.00119

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000464

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00391

AC:

209

AN:

53406

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00713

AC:

7927

AN:

1112010

Other (OTH)

AF:

0.00560

AC:

338

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

559

1119

1678

2238

2797

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

286

572

858

1144

1430

<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:

0.00396

AC:

602

AN:

152158

Hom.:

Cov.:

AF XY:

0.00370

AC XY:

275

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.000867

AC:

AN:

41500

American (AMR)

AF:

0.00111

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.000417

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00387

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00723

AC:

492

AN:

68022

Other (OTH)

AF:

0.00380

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

122

153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00621

Hom.:

Bravo

AF:

0.00334

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00756

AC:

ExAC

AF:

0.00396

AC:

481

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00589

EpiControl

AF:

0.00569

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

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

- -

Nov 29, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32859249) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EVC2: BS2 -

Ellis-van Creveld syndrome

Uncertain:1Benign:1

Sep 01, 2017

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This mutation was found once in our laboratory in trans with another variant in a 3-year-old male with ectodermal dysplasia. Heterozygotes would be expected to be asymptomatic carriers. -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:1

Feb 11, 2015

Eurofins Ntd Llc (ga)

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

- -

EVC2-related disorder

Benign:1

Nov 09, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.0094

T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Uncertain

2.3

M;.

PhyloP100

4.6

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.35

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.98

D;.

Vest4

0.55

MVP

0.87

MPC

0.14

ClinPred

0.023

GERP RS

3.3

Varity_R

0.18

gMVP

0.45

Mutation Taster

=96/4

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