rs113869406

Positions:

• chr4-5628715-A-G

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.1730T>C​(p.Met577Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0017 in 1,612,242 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (18 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.95

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=0.010639936).
• BP6: Variant 4-5628715-A-G is Benign according to our data. Variant chr4-5628715-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 349080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5628715-A-G is described in Lovd as [Benign]. Variant chr4-5628715-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00531 (799/150466) while in subpopulation AFR AF= 0.0155 (628/40410). AF 95% confidence interval is 0.0145. There are 7 homozygotes in gnomad4. There are 398 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC2	NM_147127.5	c.1730T>C	p.Met577Thr	missense_variant	12/22	ENST00000344408.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC2	ENST00000344408.10	c.1730T>C	p.Met577Thr	missense_variant	12/22	1	NM_147127.5	P2
EVC2	ENST00000310917.6	c.1490T>C	p.Met497Thr	missense_variant	12/22	1		A2
EVC2	ENST00000475313.5	c.1490T>C	p.Met497Thr	missense_variant, NMD_transcript_variant	12/23	1
EVC2	ENST00000509670.1	c.*123T>C		3_prime_UTR_variant, NMD_transcript_variant	13/23	1

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 796 AN: 150348 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00551

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000838

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.000736

Gnomad OTH AF: 0.00632

GnomAD3 exomes AF: 0.00231 AC: 582 AN: 251416 Hom.: 5 AF XY: 0.00196 AC XY: 266 AN XY: 135894

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000905

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00132 AC: 1934 AN: 1461776 Hom.: 18 Cov.: 31 AF XY: 0.00131 AC XY: 951 AN XY: 727192

Gnomad4 AFR exome AF: 0.0164

Gnomad4 AMR exome AF: 0.00373

Gnomad4 ASJ exome AF: 0.00467

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.000676

Gnomad4 OTH exome AF: 0.00298

GnomAD4 genome AF: 0.00531 AC: 799 AN: 150466 Hom.: 7 Cov.: 32 AF XY: 0.00542 AC XY: 398 AN XY: 73464

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.00551

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000838

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000736

Gnomad4 OTH AF: 0.00625

Alfa AF: 0.00175 Hom.: 2

Bravo AF: 0.00626

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00226 AC: 274

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00219

ClinVar

Significance: Benign/Likely 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
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	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 20, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2017	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;C0457013:Curry-Hall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.62	T;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.086	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		1.0	D;.
Vest4		0.86
MVP		0.84
MPC		0.15
ClinPred		0.024	T
GERP RS		4.9
Varity_R		0.59
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs113869406; hg19: chr4-5630442;