chr4-5685483-C-T

Position:

chr4-5685483-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_147127.5(EVC2):c.707-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00404 in 1,613,818 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 20 hom. )

Consequence

EVC2
NM_147127.5 splice_region, intron

Scores

Splicing: ADA: 0.000008120

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.435

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 (BayesDel_noAF=-0.73).

BP6

Variant 4-5685483-C-T is Benign according to our data. Variant chr4-5685483-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 288144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5685483-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00329 (501/152338) while in subpopulation NFE AF= 0.00526 (358/68038). AF 95% confidence interval is 0.00481. There are 2 homozygotes in gnomad4. There are 231 alleles in male gnomad4 subpopulation. Median coverage is 33. 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 link	c.707-4G>A		splice_region_variant, intron_variant		ENST00000344408.10	NP_667338.3	Q86UK5-1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
EVC2	ENST00000344408.10 link	c.707-4G>A	splice_region_variant, intron_variant	1	NM_147127.5	ENSP00000342144.5	Q86UK5-1
EVC2	ENST00000310917.6 link	c.467-4G>A	splice_region_variant, intron_variant	1		ENSP00000311683.2	Q86UK5-2
EVC2	ENST00000475313.5 link	n.467-4G>A	splice_region_variant, intron_variant	1		ENSP00000431981.1	A0A0C4DGE7
EVC2	ENST00000509670.1 link	n.467-4G>A	splice_region_variant, intron_variant	1		ENSP00000423876.1	E9PFT2

Frequencies

GnomAD3 genomes

AF:

0.00330

AC:

502

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00528

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00357

AC:

897

AN:

251164

Hom.:

AF XY:

0.00338

AC XY:

459

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00359

Gnomad ASJ exome

AF:

0.00506

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00118

Gnomad FIN exome

AF:

0.00135

Gnomad NFE exome

AF:

0.00539

Gnomad OTH exome

AF:

0.00457

GnomAD4 exome

AF:

0.00412

AC:

6014

AN:

1461480

Hom.:

Cov.:

AF XY:

0.00404

AC XY:

2934

AN XY:

727056

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.00340

Gnomad4 ASJ exome

AF:

0.00490

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000823

Gnomad4 FIN exome

AF:

0.00107

Gnomad4 NFE exome

AF:

0.00480

Gnomad4 OTH exome

AF:

0.00378

GnomAD4 genome

AF:

0.00329

AC:

501

AN:

152338

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

231

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00526

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00373

Hom.:

Bravo

AF:

0.00323

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00545

EpiControl

AF:

0.00539

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	EVC2: BP4, BS2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 19, 2016

- -

Ellis-van Creveld syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

2.3

DANN

Benign

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000081

dbscSNV1_RF

Benign

0.0

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