4-5562851-G-C

Variant names:

• chr4-5562851-G-C
• rs1277969148
• NM_147127.5:c.3924C>G

Variant summary

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

The NM_147127.5(EVC2):​c.3924C>G​(p.Asp1308Glu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46

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=0.1378125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5	c.3924C>G	p.Asp1308Glu	missense_variant	Exon 22 of 22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.3924C>G	p.Asp1308Glu	missense_variant	Exon 22 of 22	1	NM_147127.5	ENSP00000342144.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T;.
Eigen	Benign	-0.064
Eigen_PC	Benign	0.0061
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.028	D;D
Polyphen		0.61	P;.
Vest4		0.16
MutPred		0.17		Gain of methylation at R1303 (P = 0.1179);.;
MVP		0.56
MPC		0.047
ClinPred		0.34	T
GERP RS		3.4
Varity_R		0.13
gMVP		0.14

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: rs1277969148; hg19: chr4-5564578;