rs60809236

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_147127.5(EVC2):c.3023C>T(p.Ser1008Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00618 in 1,613,748 control chromosomes in the GnomAD database, including 498 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. S1008W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.032 ( 258 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 240 hom. )

Consequence

EVC2
NM_147127.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.30

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022625625).

BP6

Variant 4-5584657-G-A is Benign according to our data. Variant chr4-5584657-G-A is described in ClinVar as [Benign]. Clinvar id is 262615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5584657-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC2	NM_147127.5 linkuse as main transcript	c.3023C>T	p.Ser1008Leu	missense_variant	17/22	ENST00000344408.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC2	ENST00000344408.10 linkuse as main transcript	c.3023C>T	p.Ser1008Leu	missense_variant	17/22	1	NM_147127.5	P2	Q86UK5-1
EVC2	ENST00000310917.6 linkuse as main transcript	c.2783C>T	p.Ser928Leu	missense_variant	17/22	1		A2	Q86UK5-2
EVC2	ENST00000475313.5 linkuse as main transcript	c.2783C>T	p.Ser928Leu	missense_variant, NMD_transcript_variant	17/23	1
EVC2	ENST00000509670.1 linkuse as main transcript	c.*1416C>T		3_prime_UTR_variant, NMD_transcript_variant	18/23	1

Frequencies

GnomAD3 genomes

AF:

0.0318

AC:

4836

AN:

152046

Hom.:

254

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000514

Gnomad OTH

AF:

0.0291

GnomAD3 exomes

AF:

0.00903

AC:

2261

AN:

250334

Hom.:

111

AF XY:

0.00658

AC XY:

890

AN XY:

135322

show subpopulations

Gnomad AFR exome

AF:

0.117

Gnomad AMR exome

AF:

0.00779

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000197

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000575

Gnomad OTH exome

AF:

0.00572

GnomAD4 exome

AF:

0.00351

AC:

5124

AN:

1461584

Hom.:

240

Cov.:

AF XY:

0.00314

AC XY:

2283

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.113

Gnomad4 AMR exome

AF:

0.00852

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000346

Gnomad4 OTH exome

AF:

0.00821

GnomAD4 genome

AF:

0.0319

AC:

4856

AN:

152164

Hom.:

258

Cov.:

AF XY:

0.0306

AC XY:

2276

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.109

Gnomad4 AMR

AF:

0.0141

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.0288

Alfa

AF:

0.00478

Hom.:

Bravo

AF:

0.0377

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.104

AC:

458

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0110

AC:

1339

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000713

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2016	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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Ellis-van Creveld syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

-0.61

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.050

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.76

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.41

N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.14

Sift

Benign

0.34

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.014

B;.

Vest4

0.045

MPC

0.020

ClinPred

0.0076

GERP RS

-0.13

Varity_R

0.052

gMVP

0.086

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over