chr4-5689175-T-A

Position:

• chr4-5689175-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_147127.5(EVC2):​c.688A>T​(p.Ser230Cys) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S230G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22189257).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC2	NM_147127.5	c.688A>T	p.Ser230Cys	missense_variant	5/22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.688A>T	p.Ser230Cys	missense_variant	5/22	1	NM_147127.5	ENSP00000342144.5
EVC2	ENST00000310917.6	c.448A>T	p.Ser150Cys	missense_variant	5/22	1		ENSP00000311683.2
EVC2	ENST00000475313.5	n.448A>T		non_coding_transcript_exon_variant	5/23	1		ENSP00000431981.1
EVC2	ENST00000509670.1	n.448A>T		non_coding_transcript_exon_variant	6/23	1		ENSP00000423876.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.056	T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.28
Sift	Uncertain	0.021	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.91	P;.
Vest4		0.32
MutPred		0.37		Gain of methylation at K231 (P = 0.0155);.;
MVP		0.76
MPC		0.061
ClinPred		0.36	T
GERP RS		1.9
Varity_R		0.090
gMVP		0.47

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: rs4689278; hg19: chr4-5690902;