rs2279252

Variant names:

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.2279G>A(p.Arg760Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,611,026 control chromosomes in the GnomAD database, including 479 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R760W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.016 ( 32 hom., cov: 33)

Exomes 𝑓: 0.017 ( 447 hom. )

Consequence

EVC
NM_153717.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.929

Publications

12 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=0.0017463267).

BP6

Variant 4-5798767-G-A is Benign according to our data. Variant chr4-5798767-G-A is described in ClinVar as Benign. ClinVar VariationId is 262771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC	NM_153717.3 link	c.2279G>A	p.Arg760Gln	missense_variant	Exon 15 of 21	ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
EVC	ENST00000264956.11 link	c.2279G>A	p.Arg760Gln	missense_variant	Exon 15 of 21	1	NM_153717.3	ENSP00000264956.6
EVC	ENST00000515113.1 link	n.503G>A		non_coding_transcript_exon_variant	Exon 3 of 4	5
CRMP1	ENST00000506216.5 link	n.1647+26727C>T		intron_variant	Intron 12 of 12	5

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2417

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00364

Gnomad AMI

AF:

0.0593

Gnomad AMR

AF:

0.0296

Gnomad ASJ

AF:

0.00923

Gnomad EAS

AF:

0.0471

Gnomad SAS

AF:

0.0446

Gnomad FIN

AF:

0.0297

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0133

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.0248

AC:

6068

AN:

244388

AF XY:

0.0251

show subpopulations

Gnomad AFR exome

AF:

0.00339

Gnomad AMR exome

AF:

0.0392

Gnomad ASJ exome

AF:

0.00937

Gnomad EAS exome

AF:

0.0469

Gnomad FIN exome

AF:

0.0313

Gnomad NFE exome

AF:

0.0139

Gnomad OTH exome

AF:

0.0205

GnomAD4 exome

AF:

0.0173

AC:

25215

AN:

1458730

Hom.:

447

Cov.:

AF XY:

0.0181

AC XY:

13164

AN XY:

725654

show subpopulations

African (AFR)

AF:

0.00218

AC:

AN:

33412

American (AMR)

AF:

0.0374

AC:

1671

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00846

AC:

221

AN:

26130

East Asian (EAS)

AF:

0.0713

AC:

2832

AN:

39692

South Asian (SAS)

AF:

0.0456

AC:

3923

AN:

86036

European-Finnish (FIN)

AF:

0.0302

AC:

1583

AN:

52468

Middle Eastern (MID)

AF:

0.0202

AC:

AN:

4210

European-Non Finnish (NFE)

AF:

0.0124

AC:

13763

AN:

1111900

Other (OTH)

AF:

0.0177

AC:

1064

AN:

60212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1687

3373

5060

6746

8433

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

600

1200

1800

2400

3000

<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:

0.0159

AC:

2416

AN:

152296

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

1334

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00363

AC:

151

AN:

41582

American (AMR)

AF:

0.0295

AC:

452

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00923

AC:

AN:

3468

East Asian (EAS)

AF:

0.0472

AC:

244

AN:

5166

South Asian (SAS)

AF:

0.0447

AC:

215

AN:

4814

European-Finnish (FIN)

AF:

0.0297

AC:

315

AN:

10616

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0133

AC:

903

AN:

68026

Other (OTH)

AF:

0.0203

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

120

241

361

482

602

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0141

Hom.:

Bravo

AF:

0.0149

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00252

AC:

ESP6500EA

AF:

0.0142

AC:

121

ExAC

AF:

0.0237

AC:

2870

Asia WGS

AF:

0.0380

AC:

130

AN:

3478

EpiCase

AF:

0.0133

EpiControl

AF:

0.0136

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Aug 04, 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. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 19, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Benign:1

Jan 30, 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 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

0.13

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

0.93

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.95

REVEL

Benign

0.14

Sift

Benign

0.21

Sift4G

Benign

0.10

Polyphen

0.93

Vest4

0.037

ClinPred

0.013

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.046

gMVP

0.13

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