rs73063795

Positions:

• chr4-5640600-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_147127.5(EVC2):​c.1384A>G​(p.Thr462Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,614,130 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (26 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.552

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 (MetaRNN=0.0046666563).
• BP6: Variant 4-5640600-T-C is Benign according to our data. Variant chr4-5640600-T-C is described in ClinVar as [Benign]. Clinvar id is 235428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5640600-T-C is described in Lovd as [Benign]. Variant chr4-5640600-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0115 (1745/152244) while in subpopulation AFR AF= 0.0332 (1377/41530). AF 95% confidence interval is 0.0317. There are 27 homozygotes in gnomad4. There are 845 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC2	NM_147127.5	c.1384A>G	p.Thr462Ala	missense_variant	10/22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.1384A>G	p.Thr462Ala	missense_variant	10/22	1	NM_147127.5	ENSP00000342144.5
EVC2	ENST00000310917.6	c.1144A>G	p.Thr382Ala	missense_variant	10/22	1		ENSP00000311683.2
EVC2	ENST00000475313.5	n.1144A>G		non_coding_transcript_exon_variant	10/23	1		ENSP00000431981.1
EVC2	ENST00000509670.1	n.1144A>G		non_coding_transcript_exon_variant	11/23	1		ENSP00000423876.1

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1727 AN: 152126 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00433 AC: 1089 AN: 251470 Hom.: 10 AF XY: 0.00361 AC XY: 490 AN XY: 135908

Gnomad AFR exome AF: 0.0330

Gnomad AMR exome AF: 0.00804

Gnomad ASJ exome AF: 0.00704

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.00212 AC: 3096 AN: 1461886 Hom.: 26 Cov.: 34 AF XY: 0.00199 AC XY: 1447 AN XY: 727242

Gnomad4 AFR exome AF: 0.0340

Gnomad4 AMR exome AF: 0.00827

Gnomad4 ASJ exome AF: 0.00658

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000933

Gnomad4 OTH exome AF: 0.00512

GnomAD4 genome AF: 0.0115 AC: 1745 AN: 152244 Hom.: 27 Cov.: 32 AF XY: 0.0113 AC XY: 845 AN XY: 74452

Gnomad4 AFR AF: 0.0332

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.00519 Hom.: 4

Bravo AF: 0.0130

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0329 AC: 145

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00435 AC: 528

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00172

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Ellis-van Creveld syndrome Benign:1

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 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.0
DANN	Benign	0.97
DEOGEN2	Uncertain	0.49	T;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.48	T;T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.25
Sift	Benign	0.062	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.45	P;.
Vest4		0.085
MVP		0.68
MPC		0.020
ClinPred		0.011	T
GERP RS		-4.3
Varity_R		0.057
gMVP		0.28

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

Other links and lift over

dbSNP: rs73063795; hg19: chr4-5642327; COSMIC: COSV99049296;