NM_147127.5:c.1823G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_147127.5(EVC2):c.1823G>A(p.Arg608His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,972 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R608C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 5 hom. )

Consequence

EVC2
NM_147127.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:5

Conservation

PhyloP100: 0.347

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

acrofacial dysostosis, Weyers type
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
Ellis-van Creveld syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine

EVC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068377852).

BP6

Variant 4-5628622-C-T is Benign according to our data. Variant chr4-5628622-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 281122.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_147127.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	NM_147127.5	MANE Select	c.1823G>A	p.Arg608His	missense	Exon 12 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.1583G>A	p.Arg528His	missense	Exon 12 of 22	NP_001159608.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EVC2	ENST00000344408.10	TSL:1 MANE Select	c.1823G>A	p.Arg608His	missense	Exon 12 of 22	ENSP00000342144.5
EVC2	ENST00000310917.6	TSL:1	c.1583G>A	p.Arg528His	missense	Exon 12 of 22	ENSP00000311683.2
EVC2	ENST00000475313.5	TSL:1	n.1583G>A		non_coding_transcript_exon	Exon 12 of 23	ENSP00000431981.1

Frequencies

GnomAD3 genomes

AF:

0.00125

AC:

190

AN:

151986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000984

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00171

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00150

AC:

377

AN:

251480

AF XY:

0.00149

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.0115

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00183

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00179

AC:

2618

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

1293

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.000827

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0126

AC:

330

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000128

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000356

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00191

AC:

2121

AN:

1111994

Other (OTH)

AF:

0.00152

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

151

302

452

603

754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<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:

0.00125

AC:

190

AN:

152104

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41496

American (AMR)

AF:

0.000982

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000378

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00171

AC:

116

AN:

67986

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00183

Hom.:

Bravo

AF:

0.00117

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00143

AC:

174

EpiCase

AF:

0.00147

EpiControl

AF:

0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Jan 18, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29068549)

Sep 27, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 16, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 30, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EVC2: BP4, BS1

Type IV short rib polydactyly syndrome

Pathogenic:1Uncertain:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Jun 01, 2017

Dan Cohn Lab, University Of California Los Angeles

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

Ellis-van Creveld syndrome

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EVC2-related disorder

Benign:1

Mar 13, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Benign

-0.022

Eigen_PC

Benign

0.0019

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.78

M_CAP

Benign

0.049

MetaRNN

Benign

0.0068

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.0

PhyloP100

0.35

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.63

REVEL

Benign

0.18

Sift

Benign

0.48

Sift4G

Benign

0.21

Polyphen

0.64

Vest4

0.49

MVP

0.83

MPC

0.18

ClinPred

0.034

GERP RS

4.0

Varity_R

0.052

gMVP

0.10

Mutation Taster

=89/11

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over