4-5628622-C-G

Variant names:

• chr4-5628622-C-G
• rs145693546
• NM_147127.5:c.1823G>C

Variant summary

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

The NM_147127.5(EVC2):​c.1823G>C​(p.Arg608Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R608H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.347

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5	c.1823G>C	p.Arg608Pro	missense_variant	Exon 12 of 22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.1823G>C	p.Arg608Pro	missense_variant	Exon 12 of 22	1	NM_147127.5	ENSP00000342144.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.44
Sift	Benign	0.18	T;T
Sift4G	Benign	0.075	T;T
Polyphen		1.0	D;.
Vest4		0.70
MutPred		0.28		Loss of catalytic residue at R608 (P = 0.0392);.;
MVP		0.85
MPC		0.19
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.64
gMVP		0.52

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: rs145693546; hg19: chr4-5630349;