rs544397395

Positions:

chr4-5708392-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_147127.5(EVC2):c.122C>A(p.Pro41His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 1,496,282 control chromosomes in the GnomAD database, including 24 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 22 hom. )

Consequence

EVC2
NM_147127.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 0.448

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061277747).

BP6

Variant 4-5708392-G-T is Benign according to our data. Variant chr4-5708392-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193503.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1, Benign=1}. Variant chr4-5708392-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00281 (428/152100) while in subpopulation NFE AF= 0.00453 (308/67948). AF 95% confidence interval is 0.00412. There are 2 homozygotes in gnomad4. There are 184 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC2	NM_147127.5 linkuse as main transcript	c.122C>A	p.Pro41His	missense_variant	1/22	ENST00000344408.10	NP_667338.3	Q86UK5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EVC2	ENST00000344408.10 linkuse as main transcript	c.122C>A	p.Pro41His	missense_variant	1/22	1	NM_147127.5	ENSP00000342144.5	Q86UK5-1
EVC2	ENST00000310917.6 linkuse as main transcript	c.-13+437C>A		intron_variant		1		ENSP00000311683.2	Q86UK5-2
EVC2	ENST00000475313.5 linkuse as main transcript	n.-13+437C>A		intron_variant		1		ENSP00000431981.1	A0A0C4DGE7
EVC2	ENST00000509670.1 linkuse as main transcript	n.-106-252C>A		intron_variant		1		ENSP00000423876.1	E9PFT2

Frequencies

GnomAD3 genomes

AF:

0.00282

AC:

428

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000821

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00453

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00361

AC:

331

AN:

91778

Hom.:

AF XY:

0.00352

AC XY:

182

AN XY:

51648

show subpopulations

Gnomad AFR exome

AF:

0.000659

Gnomad AMR exome

AF:

0.00157

Gnomad ASJ exome

AF:

0.0179

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000588

Gnomad NFE exome

AF:

0.00522

Gnomad OTH exome

AF:

0.00426

GnomAD4 exome

AF:

0.00484

AC:

6506

AN:

1344182

Hom.:

Cov.:

AF XY:

0.00470

AC XY:

3115

AN XY:

662254

show subpopulations

Gnomad4 AFR exome

AF:

0.000698

Gnomad4 AMR exome

AF:

0.00135

Gnomad4 ASJ exome

AF:

0.0188

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000660

Gnomad4 NFE exome

AF:

0.00540

Gnomad4 OTH exome

AF:

0.00444

GnomAD4 genome

AF:

0.00281

AC:

428

AN:

152100

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

184

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.000819

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.0176

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00453

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00459

Hom.:

Bravo

AF:

0.00280

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00441

AC:

ExAC

AF:

0.00155

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Ellis-van Creveld syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Curry-Hall syndrome

Benign:1

Likely 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

0.11

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.018

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0061

MetaSVM

Benign

-0.41

MutationAssessor

Benign

0.90

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.42

REVEL

Benign

0.28

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.14

MVP

0.77

MPC

0.11

ClinPred

0.033

GERP RS

1.9

Varity_R

0.065

gMVP

0.15

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