Genetic Variant EVC2:p.His1169Gln (chr4-5568494-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_147127.5(EVC2):c.3507C>G(p.His1169Gln) 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. 16/22 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. H1169Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Consequence

EVC2
NM_147127.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.586

Publications

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

EVC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14592275).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	NM_147127.5	MANE Select	c.3507C>G	p.His1169Gln	missense	Exon 20 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.3267C>G	p.His1089Gln	missense	Exon 20 of 22	NP_001159608.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EVC2	ENST00000344408.10	TSL:1 MANE Select	c.3507C>G	p.His1169Gln	missense	Exon 20 of 22	ENSP00000342144.5
EVC2	ENST00000310917.6	TSL:1	c.3267C>G	p.His1089Gln	missense	Exon 20 of 22	ENSP00000311683.2
EVC2	ENST00000475313.5	TSL:1	n.3267C>G		non_coding_transcript_exon	Exon 20 of 23	ENSP00000431981.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

21445

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

CADD

Benign

1.3

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.062

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.35

M_CAP

Benign

0.035

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.9

PhyloP100

0.59

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.6

REVEL

Benign

0.23

Sift

Benign

0.15

Sift4G

Benign

0.16

Polyphen

0.81

Vest4

0.38

MutPred

0.082

Gain of loop (P = 0.1081)

MVP

0.70

MPC

0.046

ClinPred

0.16

GERP RS

3.5

Varity_R

0.054

gMVP

0.092

Mutation Taster

=91/9

polymorphism

(source)

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

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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