rs6820907

Positions:

chr4-5708462-G-A

Variant summary

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

The ENST00000344408.10(EVC2):c.52C>T(p.Leu18Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,505,760 control chromosomes in the GnomAD database, including 15,591 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. L18L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.18 ( 2994 hom., cov: 32)

Exomes 𝑓: 0.13 ( 12597 hom. )

Consequence

EVC2
ENST00000344408.10 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0250

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=0.004922539).

BP6

Variant 4-5708462-G-A is Benign according to our data. Variant chr4-5708462-G-A is described in ClinVar as [Benign]. Clinvar id is 262618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5708462-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.297 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.52C>T	p.Leu18Phe	missense_variant	1/22	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.52C>T	p.Leu18Phe	missense_variant	1/22	1	NM_147127.5	ENSP00000342144	P2	Q86UK5-1
EVC2	ENST00000310917.6 linkuse as main transcript	c.-13+367C>T		intron_variant		1		ENSP00000311683	A2	Q86UK5-2
EVC2	ENST00000475313.5 linkuse as main transcript	c.-13+367C>T		intron_variant, NMD_transcript_variant		1		ENSP00000431981
EVC2	ENST00000509670.1 linkuse as main transcript	c.-106-322C>T		intron_variant, NMD_transcript_variant		1		ENSP00000423876

Frequencies

GnomAD3 genomes

AF:

0.178

AC:

26979

AN:

151866

Hom.:

2982

Cov.:

show subpopulations

Gnomad AFR

AF:

0.302

Gnomad AMI

AF:

0.296

Gnomad AMR

AF:

0.189

Gnomad ASJ

AF:

0.104

Gnomad EAS

AF:

0.177

Gnomad SAS

AF:

0.191

Gnomad FIN

AF:

0.113

Gnomad MID

AF:

0.102

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.160

GnomAD3 exomes

AF:

0.152

AC:

15220

AN:

100284

Hom.:

1345

AF XY:

0.149

AC XY:

8348

AN XY:

56038

show subpopulations

Gnomad AFR exome

AF:

0.291

Gnomad AMR exome

AF:

0.210

Gnomad ASJ exome

AF:

0.0984

Gnomad EAS exome

AF:

0.145

Gnomad SAS exome

AF:

0.186

Gnomad FIN exome

AF:

0.120

Gnomad NFE exome

AF:

0.111

Gnomad OTH exome

AF:

0.129

GnomAD4 exome

AF:

0.128

AC:

173268

AN:

1353784

Hom.:

12597

Cov.:

AF XY:

0.129

AC XY:

85908

AN XY:

667562

show subpopulations

Gnomad4 AFR exome

AF:

0.311

Gnomad4 AMR exome

AF:

0.208

Gnomad4 ASJ exome

AF:

0.103

Gnomad4 EAS exome

AF:

0.244

Gnomad4 SAS exome

AF:

0.187

Gnomad4 FIN exome

AF:

0.122

Gnomad4 NFE exome

AF:

0.114

Gnomad4 OTH exome

AF:

0.134

GnomAD4 genome

AF:

0.178

AC:

27045

AN:

151976

Hom.:

2994

Cov.:

AF XY:

0.179

AC XY:

13287

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.302

Gnomad4 AMR

AF:

0.189

Gnomad4 ASJ

AF:

0.104

Gnomad4 EAS

AF:

0.177

Gnomad4 SAS

AF:

0.192

Gnomad4 FIN

AF:

0.113

Gnomad4 NFE

AF:

0.112

Gnomad4 OTH

AF:

0.165

Alfa

AF:

0.0792

Hom.:

153

Bravo

AF:

0.187

TwinsUK

AF:

0.115

AC:

428

ALSPAC

AF:

0.118

AC:

455

ExAC

AF:

0.0976

AC:

2186

Asia WGS

AF:

0.237

AC:

824

AN:

3470

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2015	- -

Ellis-van Creveld syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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

- -

Curry-Hall syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.046

Eigen

Benign

-0.86

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0049

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.85

REVEL

Benign

0.24

Sift

Benign

0.075

Sift4G

Uncertain

0.036

Polyphen

0.72

Vest4

0.029

MPC

0.021

ClinPred

0.0030

GERP RS

-1.8

Varity_R

0.063

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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