chr4-5708528-C-T

Position:

• chr4-5708528-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_147127.5(EVC2):​c.-15G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0833 in 1,433,358 control chromosomes in the GnomAD database, including 5,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (585 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5157 hom.)
• Consequence: EVC2 NM_147127.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.62

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-5708528-C-T is Benign according to our data. Variant chr4-5708528-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 262603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5708528-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC2	NM_147127.5	c.-15G>A		5_prime_UTR_variant	1/22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.-15G>A		5_prime_UTR_variant	1/22	1	NM_147127.5	ENSP00000342144.5
EVC2	ENST00000310917.6	c.-13+301G>A		intron_variant		1		ENSP00000311683.2
EVC2	ENST00000475313.5	n.-13+301G>A		intron_variant		1		ENSP00000431981.1
EVC2	ENST00000509670.1	n.-107+301G>A		intron_variant		1		ENSP00000423876.1

Frequencies

GnomAD3 genomes AF: 0.0757 AC: 11509 AN: 152036 Hom.: 585 Cov.: 32

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.0744

Gnomad MID AF: 0.175

Gnomad NFE AF: 0.0782

Gnomad OTH AF: 0.0876

GnomAD3 exomes AF: 0.133 AC: 6690 AN: 50152 Hom.: 475 AF XY: 0.131 AC XY: 3915 AN XY: 29908

Gnomad AFR exome AF: 0.0405

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.259

Gnomad SAS exome AF: 0.162

Gnomad FIN exome AF: 0.0815

Gnomad NFE exome AF: 0.0865

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.0842 AC: 107897 AN: 1281208 Hom.: 5157 Cov.: 28 AF XY: 0.0853 AC XY: 53665 AN XY: 628894

Gnomad4 AFR exome AF: 0.0278

Gnomad4 AMR exome AF: 0.154

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.0750

Gnomad4 NFE exome AF: 0.0765

Gnomad4 OTH exome AF: 0.0909

GnomAD4 genome AF: 0.0756 AC: 11505 AN: 152150 Hom.: 585 Cov.: 32 AF XY: 0.0777 AC XY: 5781 AN XY: 74396

Gnomad4 AFR AF: 0.0275

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.218

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.0744

Gnomad4 NFE AF: 0.0782

Gnomad4 OTH AF: 0.0866

Alfa AF: 0.0317 Hom.: 26

Bravo AF: 0.0807

Asia WGS AF: 0.143 AC: 497 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 15, 2016	- -

Ellis-van Creveld syndrome Benign:2

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

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Curry-Hall syndrome Benign:1

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
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.15
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs76269601; hg19: chr4-5710255; COSMIC: COSV99382289; COSMIC: COSV99382289;