rs557830930

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_147127.5(EVC2):c.92T>C(p.Leu31Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 1,503,748 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L31L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00090 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 4 hom. )

Consequence

EVC2
NM_147127.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: -1.13

Publications

0 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003951043).

BP6

Variant 4-5708422-A-G is Benign according to our data. Variant chr4-5708422-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285109.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000901 (137/152054) while in subpopulation AMR AF = 0.00471 (72/15302). AF 95% confidence interval is 0.00383. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5 link	c.92T>C	p.Leu31Pro	missense_variant	Exon 1 of 22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
EVC2	ENST00000344408.10 link	c.92T>C	p.Leu31Pro	missense_variant	Exon 1 of 22	1	NM_147127.5	ENSP00000342144.5
EVC2	ENST00000310917.6 link	c.-13+407T>C		intron_variant	Intron 1 of 21	1		ENSP00000311683.2
EVC2	ENST00000475313.5 link	n.-13+407T>C		intron_variant	Intron 1 of 22	1		ENSP00000431981.1
EVC2	ENST00000509670.1 link	n.-106-282T>C		intron_variant	Intron 1 of 22	1		ENSP00000423876.1

Frequencies

GnomAD3 genomes

AF:

0.000902

AC:

137

AN:

151940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00129

AC:

127

AN:

98786

AF XY:

0.00114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.00694

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000758

Gnomad OTH exome

AF:

0.00230

GnomAD4 exome

AF:

0.000601

AC:

813

AN:

1351694

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

394

AN XY:

666358

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

27564

American (AMR)

AF:

0.00217

AC:

AN:

32678

Ashkenazi Jewish (ASJ)

AF:

0.00583

AC:

140

AN:

24002

East Asian (EAS)

AF:

0.00

AC:

AN:

31672

South Asian (SAS)

AF:

0.00

AC:

AN:

76066

European-Finnish (FIN)

AF:

0.0000599

AC:

AN:

33404

Middle Eastern (MID)

AF:

0.00511

AC:

AN:

4112

European-Non Finnish (NFE)

AF:

0.000430

AC:

458

AN:

1065768

Other (OTH)

AF:

0.00190

AC:

107

AN:

56428

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

129

172

215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.000901

AC:

137

AN:

152054

Hom.:

Cov.:

AF XY:

0.000780

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41510

American (AMR)

AF:

0.00471

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5104

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000515

AC:

AN:

67920

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

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:

0.00120

Hom.:

Bravo

AF:

0.00121

ExAC

AF:

0.000694

AC:

Asia WGS

AF:

0.000868

AC:

AN:

3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 21, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Sep 29, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.92T>C (p.L31P) alteration is located in exon 1 (coding exon 1) of the EVC2 gene. This alteration results from a T to C substitution at nucleotide position 92, causing the leucine (L) at amino acid position 31 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Ellis-van Creveld syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

EVC2-related disorder

Benign:1

Apr 15, 2020

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). -

Curry-Hall syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.36

CADD

Benign

9.5

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.017

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0089

LIST_S2

Benign

0.25

M_CAP

Benign

0.014

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.69

PhyloP100

-1.1

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.43

REVEL

Benign

0.13

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0020

Vest4

0.31

MutPred

0.22

Loss of catalytic residue at L31 (P = 0.0331);

MVP

0.45

MPC

0.024

ClinPred

0.028

GERP RS

-0.73

PromoterAI

-0.020

Neutral

(source)

Varity_R

0.093

gMVP

0.18

Mutation Taster

=98/2

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