chr4-5584657-G-C

Variant names:

• chr4-5584657-G-C
• NM_147127.5:c.3023C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_147127.5(EVC2):​c.3023C>G​(p.Ser1008Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S1008L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32490095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5	c.3023C>G	p.Ser1008Trp	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.3023C>G	p.Ser1008Trp	missense_variant	Exon 17 of 22	1	NM_147127.5	ENSP00000342144.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Uncertain:1

Nov 05, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: "Deleterious"; 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. This variant has not been reported in the literature in individuals affected with EVC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 1008 of the EVC2 protein (p.Ser1008Trp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.26
Sift	Uncertain	0.019	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		1.0	D;.
Vest4		0.40
MutPred		0.35		Loss of disorder (P = 2e-04);.;
MVP		0.81
MPC		0.14
ClinPred		0.97	D
GERP RS		-0.13
Varity_R		0.23
gMVP		0.16

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-5586384;