rs2302075

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_153717.3(EVC):c.1346C>A(p.Thr449Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.8 in 1,613,976 control chromosomes in the GnomAD database, including 518,043 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. T449T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.83 ( 53273 hom., cov: 32)

Exomes 𝑓: 0.80 ( 464770 hom. )

Consequence

EVC
NM_153717.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.433

Publications

39 publications found

Variant links:

Genes affected

EVC (HGNC:3497): (EvC ciliary complex subunit 1) This gene encodes a protein containing a leucine zipper and a transmembrane domain. This gene has been implicated in both Ellis-van Creveld syndrome (EvC) and Weyers acrodental dysostosis. [provided by RefSeq, Jul 2008]

EVC links:

CRMP1 (HGNC:2365): (collapsin response mediator protein 1) This gene encodes a member of a family of cytosolic phosphoproteins expressed exclusively in the nervous system. The encoded protein is thought to be a part of the semaphorin signal transduction pathway implicated in semaphorin-induced growth cone collapse during neural development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

CRMP1 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=5.731524E-7).

BP6

Variant 4-5753815-C-A is Benign according to our data. Variant chr4-5753815-C-A is described in ClinVar as Benign. ClinVar VariationId is 167044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.948 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC	NM_153717.3 link	c.1346C>A	p.Thr449Lys	missense_variant	Exon 10 of 21	ENST00000264956.11	NP_714928.1	P57679

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EVC	ENST00000264956.11 link	c.1346C>A	p.Thr449Lys	missense_variant	Exon 10 of 21	1	NM_153717.3	ENSP00000264956.6	P57679
EVC	ENST00000509451.1 link	c.1346C>A	p.Thr449Lys	missense_variant	Exon 10 of 12	1		ENSP00000426774.1	E9PCN4
EVC	ENST00000514919.1 link	n.409C>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
CRMP1	ENST00000506216.5 link	n.1648-5503G>T		intron_variant	Intron 12 of 12	5

Frequencies

GnomAD3 genomes

AF:

0.833

AC:

126668

AN:

152046

Hom.:

53221

Cov.:

show subpopulations

Gnomad AFR

AF:

0.956

Gnomad AMI

AF:

0.785

Gnomad AMR

AF:

0.771

Gnomad ASJ

AF:

0.832

Gnomad EAS

AF:

0.819

Gnomad SAS

AF:

0.776

Gnomad FIN

AF:

0.772

Gnomad MID

AF:

0.772

Gnomad NFE

AF:

0.788

Gnomad OTH

AF:

0.822

GnomAD2 exomes

AF:

0.791

AC:

198863

AN:

251462

AF XY:

0.789

show subpopulations

Gnomad AFR exome

AF:

0.961

Gnomad AMR exome

AF:

0.713

Gnomad ASJ exome

AF:

0.827

Gnomad EAS exome

AF:

0.812

Gnomad FIN exome

AF:

0.768

Gnomad NFE exome

AF:

0.791

Gnomad OTH exome

AF:

0.784

GnomAD4 exome

AF:

0.797

AC:

1164596

AN:

1461812

Hom.:

464770

Cov.:

AF XY:

0.795

AC XY:

578466

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.961

AC:

32160

AN:

33480

American (AMR)

AF:

0.720

AC:

32206

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.831

AC:

21716

AN:

26136

East Asian (EAS)

AF:

0.814

AC:

32298

AN:

39700

South Asian (SAS)

AF:

0.781

AC:

67323

AN:

86254

European-Finnish (FIN)

AF:

0.763

AC:

40756

AN:

53408

Middle Eastern (MID)

AF:

0.760

AC:

4380

AN:

5760

European-Non Finnish (NFE)

AF:

0.796

AC:

884999

AN:

1111956

Other (OTH)

AF:

0.807

AC:

48758

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

15526

31052

46577

62103

77629

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20806

41612

62418

83224

104030

<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:

0.833

AC:

126777

AN:

152164

Hom.:

53273

Cov.:

AF XY:

0.829

AC XY:

61676

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.956

AC:

39735

AN:

41554

American (AMR)

AF:

0.770

AC:

11775

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.832

AC:

2889

AN:

3472

East Asian (EAS)

AF:

0.819

AC:

4217

AN:

5150

South Asian (SAS)

AF:

0.778

AC:

3741

AN:

4810

European-Finnish (FIN)

AF:

0.772

AC:

8180

AN:

10592

Middle Eastern (MID)

AF:

0.769

AC:

226

AN:

294

European-Non Finnish (NFE)

AF:

0.788

AC:

53558

AN:

67978

Other (OTH)

AF:

0.824

AC:

1740

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1064

2128

3192

4256

5320

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

880

1760

2640

3520

4400

<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:

0.799

Hom.:

153211

Bravo

AF:

0.839

TwinsUK

AF:

0.809

AC:

2999

ALSPAC

AF:

0.809

AC:

3119

ESP6500AA

AF:

0.954

AC:

4203

ESP6500EA

AF:

0.801

AC:

6886

ExAC

AF:

0.796

AC:

96695

Asia WGS

AF:

0.789

AC:

2746

AN:

3478

EpiCase

AF:

0.794

EpiControl

AF:

0.795

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 03, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ellis-van Creveld syndrome

Benign:4

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.44

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.062

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0022

LIST_S2

Benign

0.038

T;T

MetaRNN

Benign

5.7e-7

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.8

N;.

PhyloP100

0.43

PrimateAI

Benign

0.26

PROVEAN

Benign

1.9

N;N

REVEL

Benign

0.11

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.062

ClinPred

0.0016

GERP RS

-0.27

Varity_R

0.035

gMVP

0.047

Mutation Taster

=100/0

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