4-5568494-G-C

Position:

• chr4-5568494-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 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. Synonymous variant affecting the same amino acid position (i.e. H1169H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.586

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=0.14592275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC2	NM_147127.5	c.3507C>G	p.His1169Gln	missense_variant	20/22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.3507C>G	p.His1169Gln	missense_variant	20/22	1	NM_147127.5	ENSP00000342144.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	1.3
DANN	Benign	0.86
DEOGEN2	Benign	0.062	T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.35	T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.23
Sift	Benign	0.15	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.81	P;.
Vest4		0.38
MutPred		0.082		Gain of loop (P = 0.1081);.;
MVP		0.70
MPC		0.046
ClinPred		0.16	T
GERP RS		3.5
Varity_R		0.054
gMVP		0.092

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: rs12511039; hg19: chr4-5570221;