rs113869406

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.1730T>C(p.Met577Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0017 in 1,612,242 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M577I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0053 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 18 hom. )

Consequence

EVC2
NM_147127.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.95

Publications

5 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=0.010639936).

BP6

Variant 4-5628715-A-G is Benign according to our data. Variant chr4-5628715-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 349080.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 = 0.00531 (799/150466) while in subpopulation AFR AF = 0.0155 (628/40410). AF 95% confidence interval is 0.0145. There are 7 homozygotes in GnomAd4. There are 398 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5 link	c.1730T>C	p.Met577Thr	missense_variant	Exon 12 of 22	ENST00000344408.10	NP_667338.3	Q86UK5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10 link	c.1730T>C	p.Met577Thr	missense_variant	Exon 12 of 22	1	NM_147127.5	ENSP00000342144.5		Q86UK5-1

Frequencies

GnomAD3 genomes

AF:

0.00529

AC:

796

AN:

150348

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00551

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000838

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.000736

Gnomad OTH

AF:

0.00632

GnomAD2 exomes

AF:

0.00231

AC:

582

AN:

251416

AF XY:

0.00196

show subpopulations

Gnomad AFR exome

AF:

0.0163

Gnomad AMR exome

AF:

0.00370

Gnomad ASJ exome

AF:

0.00486

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000905

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00132

AC:

1934

AN:

1461776

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

951

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.0164

AC:

550

AN:

33478

American (AMR)

AF:

0.00373

AC:

167

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00467

AC:

122

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000563

AC:

AN:

53324

Middle Eastern (MID)

AF:

0.0226

AC:

130

AN:

5764

European-Non Finnish (NFE)

AF:

0.000676

AC:

752

AN:

1112004

Other (OTH)

AF:

0.00298

AC:

180

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

198

298

397

496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.00531

AC:

799

AN:

150466

Hom.:

Cov.:

AF XY:

0.00542

AC XY:

398

AN XY:

73464

show subpopulations

African (AFR)

AF:

0.0155

AC:

628

AN:

40410

American (AMR)

AF:

0.00551

AC:

AN:

15076

Ashkenazi Jewish (ASJ)

AF:

0.00404

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5064

South Asian (SAS)

AF:

0.000838

AC:

AN:

4772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10492

Middle Eastern (MID)

AF:

0.0240

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000736

AC:

AN:

67904

Other (OTH)

AF:

0.00625

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

115

154

192

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:

0.00236

Hom.:

Bravo

AF:

0.00626

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0138

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00226

AC:

274

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Mar 20, 2017

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Sep 07, 2017

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. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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. -

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.19

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

D;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.62

T;T

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.086

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

4.9

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

1.0

D;.

Vest4

0.86

MVP

0.84

MPC

0.15

ClinPred

0.024

GERP RS

4.9

Varity_R

0.59

gMVP

0.38

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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