rs730469

Positions:

chr4-5622943-T-C

Variant summary

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

The ENST00000344408.10(EVC2):c.2095A>G(p.Thr699Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,613,758 control chromosomes in the GnomAD database, including 94,610 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. T699T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.45 ( 18957 hom., cov: 32)

Exomes 𝑓: 0.31 ( 75653 hom. )

Consequence

EVC2
ENST00000344408.10 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.54

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=1.0240383E-6).

BP6

Variant 4-5622943-T-C is Benign according to our data. Variant chr4-5622943-T-C is described in ClinVar as [Benign]. Clinvar id is 262610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC2	NM_147127.5 linkuse as main transcript	c.2095A>G	p.Thr699Ala	missense_variant	14/22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10 linkuse as main transcript	c.2095A>G	p.Thr699Ala	missense_variant	14/22	1	NM_147127.5	ENSP00000342144	P2	Q86UK5-1
EVC2	ENST00000310917.6 linkuse as main transcript	c.1855A>G	p.Thr619Ala	missense_variant	14/22	1		ENSP00000311683	A2	Q86UK5-2
EVC2	ENST00000475313.5 linkuse as main transcript	c.1855A>G	p.Thr619Ala	missense_variant, NMD_transcript_variant	14/23	1		ENSP00000431981
EVC2	ENST00000509670.1 linkuse as main transcript	c.*488A>G		3_prime_UTR_variant, NMD_transcript_variant	15/23	1		ENSP00000423876

Frequencies

GnomAD3 genomes

AF:

0.447

AC:

67848

AN:

151906

Hom.:

18912

Cov.:

show subpopulations

Gnomad AFR

AF:

0.788

Gnomad AMI

AF:

0.248

Gnomad AMR

AF:

0.408

Gnomad ASJ

AF:

0.265

Gnomad EAS

AF:

0.610

Gnomad SAS

AF:

0.299

Gnomad FIN

AF:

0.351

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.275

Gnomad OTH

AF:

0.394

GnomAD3 exomes

AF:

0.366

AC:

91740

AN:

250438

Hom.:

19641

AF XY:

0.351

AC XY:

47524

AN XY:

135584

show subpopulations

Gnomad AFR exome

AF:

0.798

Gnomad AMR exome

AF:

0.423

Gnomad ASJ exome

AF:

0.261

Gnomad EAS exome

AF:

0.633

Gnomad SAS exome

AF:

0.289

Gnomad FIN exome

AF:

0.342

Gnomad NFE exome

AF:

0.281

Gnomad OTH exome

AF:

0.325

GnomAD4 exome

AF:

0.305

AC:

445835

AN:

1461732

Hom.:

75653

Cov.:

AF XY:

0.303

AC XY:

219983

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.807

Gnomad4 AMR exome

AF:

0.419

Gnomad4 ASJ exome

AF:

0.264

Gnomad4 EAS exome

AF:

0.609

Gnomad4 SAS exome

AF:

0.285

Gnomad4 FIN exome

AF:

0.339

Gnomad4 NFE exome

AF:

0.274

Gnomad4 OTH exome

AF:

0.329

GnomAD4 genome

AF:

0.447

AC:

67942

AN:

152026

Hom.:

18957

Cov.:

AF XY:

0.450

AC XY:

33415

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.788

Gnomad4 AMR

AF:

0.408

Gnomad4 ASJ

AF:

0.265

Gnomad4 EAS

AF:

0.610

Gnomad4 SAS

AF:

0.300

Gnomad4 FIN

AF:

0.351

Gnomad4 NFE

AF:

0.275

Gnomad4 OTH

AF:

0.389

Alfa

AF:

0.311

Hom.:

20617

Bravo

AF:

0.472

TwinsUK

AF:

0.265

AC:

983

ALSPAC

AF:

0.273

AC:

1053

ESP6500AA

AF:

0.773

AC:

3407

ESP6500EA

AF:

0.278

AC:

2393

ExAC

AF:

0.369

AC:

44836

Asia WGS

AF:

0.478

AC:

1661

AN:

3478

EpiCase

AF:

0.274

EpiControl

AF:

0.283

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	Mar 21, 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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Ellis-van Creveld syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

5.3

DANN

Benign

0.15

DEOGEN2

Benign

0.033

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.26

T;T

MetaRNN

Benign

0.0000010

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.1

N;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.36

PROVEAN

Benign

0.070

N;N

REVEL

Benign

0.16

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.011

MPC

0.020

ClinPred

0.00073

GERP RS

0.37

Varity_R

0.022

gMVP

0.039

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