Genetic Variant EVC2:p.Trp828Cys (chr4-5622554-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_147127.5(EVC2):c.2484G>T(p.Trp828Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. W828R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

EVC2
NM_147127.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.52

Publications

0 publications found

Variant links:

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]

EVC2 Gene-Disease associations (from GenCC):

acrofacial dysostosis, Weyers type
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
Ellis-van Creveld syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

EVC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.835

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_147127.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	NM_147127.5	MANE Select	c.2484G>T	p.Trp828Cys	missense	Exon 14 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.2244G>T	p.Trp748Cys	missense	Exon 14 of 22	NP_001159608.1	Q86UK5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EVC2	ENST00000344408.10	TSL:1 MANE Select	c.2484G>T	p.Trp828Cys	missense	Exon 14 of 22	ENSP00000342144.5	Q86UK5-1
EVC2	ENST00000310917.6	TSL:1	c.2244G>T	p.Trp748Cys	missense	Exon 14 of 22	ENSP00000311683.2	Q86UK5-2
EVC2	ENST00000475313.5	TSL:1	n.2244G>T		non_coding_transcript_exon	Exon 14 of 23	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.019

MutationAssessor

Uncertain

2.6

PhyloP100

4.5

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.53

Sift

Uncertain

0.011

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.73

MutPred

0.54

Gain of disorder (P = 0.0091)

MVP

0.90

MPC

0.19

ClinPred

0.98

GERP RS

5.4

Varity_R

0.34

gMVP

0.31

Mutation Taster

=38/62

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.21

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over