NM_147127.5:c.2848C>T

Variant names:

• chr4-5584832-G-A
• rs137852928
• NM_147127.5:c.2848C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_147127.5(EVC2):​c.2848C>T​(p.Arg950Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:5
• Conservation: PhyloP100: 1.23

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5	c.2848C>T	p.Arg950Trp	missense_variant	Exon 17 of 22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.2848C>T	p.Arg950Trp	missense_variant	Exon 17 of 22	1	NM_147127.5	ENSP00000342144.5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251302 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000129 AC: 189 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.000138 AC XY: 100 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000764

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74308

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000195 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ellis-van Creveld syndrome Pathogenic:1 Uncertain:2

Oct 01, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_147127.4(EVC2):c.2848C>T(R950W) is a missense variant classified as a variant of uncertain significance in the context of EVC2-related Ellis-van Creveld syndrome. R950W has been observed in cases with relevant disease (PMID: 12468274, 23220543, 32369273). Functional assessments of this variant are not available in the literature. R950W has been observed in population frequency databases (gnomAD: ASJ 0.17%). In summary, there is insufficient evidence to classify NM_147127.4(EVC2):c.2848C>T(R950W) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Dec 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function is a known mechanisms of disease in this gene and are associated with recessive Ellis-van Creveld syndrome (MIM#225500). Gain of function and dominant negative is likely the mechanism associated with dominant Weyers acrofacial dysostosis(MIM#193530) (PMID: 19810119). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (41 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (18 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as VUS in ClinVar. It has also been reported in cis with p.(Gln1089*) in two individuals with Ellis-van Creveld syndrome (PMID: 12468274, 23220543). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Uncertain:2

Oct 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 950 of the EVC2 protein (p.Arg950Trp). This variant is present in population databases (rs137852928, gnomAD 0.2%). This missense change has been observed in individual(s) with Ellis–van Creveld syndrome (PMID: 12468274, 23220543, 32369273). This variant is also known as Arg870Trp. ClinVar contains an entry for this variant (Variation ID: 3387). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jan 06, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jul 31, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with Ellis-van Creveld syndrome who also harbored a homozygous pathogenic variant on the same EVC2 allele (in cis) (PMID: 12468274); Reported along with two additional variants in the EVC2 gene in a patient with short stature, postaxial polydactyly, short ribs, and anteriorly placed anus in the published literature; however, segregation information was not provided (PMID: 23220543); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32369273, 33452237, 12468274, 23220543, 30476936) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.040
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.53
Sift	Benign	0.045	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		1.0	D;.
Vest4		0.57
MVP		0.86
MPC		0.076
ClinPred		0.27	T
GERP RS		4.1
Varity_R		0.22
gMVP		0.18

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: rs137852928; hg19: chr4-5586559; COSMIC: COSV60403853;