NM_147127.5:c.1198A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_147127.5(EVC2):c.1198A>G(p.Thr400Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,614,186 control chromosomes in the GnomAD database, including 29 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 (★★).

Frequency

Genomes: 𝑓 0.0061 ( 14 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 15 hom. )

Consequence

EVC2
NM_147127.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.38

Publications

1 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005721569).

BP6

Variant 4-5640786-T-C is Benign according to our data. Variant chr4-5640786-T-C is described in ClinVar as Benign. ClinVar VariationId is 349089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00612 (932/152302) while in subpopulation AFR AF = 0.0214 (888/41548). AF 95% confidence interval is 0.0202. There are 14 homozygotes in GnomAd4. There are 426 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5 link	c.1198A>G	p.Thr400Ala	missense_variant	Exon 10 of 22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
EVC2	ENST00000344408.10 link	c.1198A>G	p.Thr400Ala	missense_variant	Exon 10 of 22	1	NM_147127.5	ENSP00000342144.5
EVC2	ENST00000310917.6 link	c.958A>G	p.Thr320Ala	missense_variant	Exon 10 of 22	1		ENSP00000311683.2
EVC2	ENST00000475313.5 link	n.958A>G		non_coding_transcript_exon_variant	Exon 10 of 23	1		ENSP00000431981.1
EVC2	ENST00000509670.1 link	n.958A>G		non_coding_transcript_exon_variant	Exon 11 of 23	1		ENSP00000423876.1

Frequencies

GnomAD3 genomes

AF:

0.00612

AC:

932

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0214

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00163

AC:

409

AN:

251346

AF XY:

0.00124

show subpopulations

Gnomad AFR exome

AF:

0.0230

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000670

AC:

979

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

420

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0242

AC:

810

AN:

33478

American (AMR)

AF:

0.000917

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1112006

Other (OTH)

AF:

0.00157

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

134

202

269

336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00612

AC:

932

AN:

152302

Hom.:

Cov.:

AF XY:

0.00572

AC XY:

426

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0214

AC:

888

AN:

41548

American (AMR)

AF:

0.00183

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68032

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00252

Hom.:

Bravo

AF:

0.00712

ESP6500AA

AF:

0.0216

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00193

AC:

234

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 10, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Mar 28, 2017

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. -

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. -

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

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.31

T;.

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.54

T;T

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.3

M;.

PhyloP100

1.4

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.23

Sift

Benign

0.20

T;T

Sift4G

Uncertain

0.050

T;T

Polyphen

0.83

P;.

Vest4

0.11

MVP

0.75

MPC

0.026

ClinPred

0.017

GERP RS

3.0

Varity_R

0.071

gMVP

0.13

Mutation Taster

=93/7

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over