4-5622978-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_147127.5(EVC2):c.2060G>A(p.Arg687His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000671 in 1,613,612 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R687C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (2 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.386

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041615367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC2	NM_147127.5	c.2060G>A	p.Arg687His	missense_variant	14/22	ENST00000344408.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC2	ENST00000344408.10	c.2060G>A	p.Arg687His	missense_variant	14/22	1	NM_147127.5	P2
EVC2	ENST00000310917.6	c.1820G>A	p.Arg607His	missense_variant	14/22	1		A2
EVC2	ENST00000475313.5	c.1820G>A	p.Arg607His	missense_variant, NMD_transcript_variant	14/23	1
EVC2	ENST00000509670.1	c.*453G>A		3_prime_UTR_variant, NMD_transcript_variant	15/23	1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000539 AC: 134 AN: 248766 Hom.: 0 AF XY: 0.000622 AC XY: 84 AN XY: 134952

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000805

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000701 AC: 1025 AN: 1461334 Hom.: 2 Cov.: 35 AF XY: 0.000708 AC XY: 515 AN XY: 726998

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00104

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.000781

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74462

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000557 Hom.: 0

Bravo AF: 0.000344

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000815 AC: 7

ExAC AF: 0.000577 AC: 70

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 21, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 687 of the EVC2 protein (p.Arg687His). This variant is present in population databases (rs144420242, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with EVC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 429228). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 01, 2021	- -

Ellis-van Creveld syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 02, 2017

The R687H variant has not been published in association with a skeletal dysplasia to our knowledge. The R687H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R687H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret this as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-0.0011
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.042	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.26
Sift	Uncertain	0.026	D;D
Sift4G	Uncertain	0.053	T;D
Polyphen		0.99	D;.
Vest4		0.28
MVP		0.86
MPC		0.13
ClinPred		0.10	T
GERP RS		4.3
Varity_R		0.060
gMVP		0.10

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: rs144420242; hg19: chr4-5624705; COSMIC: COSV60387953;