4-5663228-T-C

Variant names:

• chr4-5663228-T-C
• rs767072839
• NM_147127.5:c.1024A>G

Variant summary

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

The NM_147127.5(EVC2):​c.1024A>G​(p.Lys342Glu) 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.81

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.1024A>G	p.Lys342Glu	missense_variant	Exon 9 of 22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.1024A>G	p.Lys342Glu	missense_variant	Exon 9 of 22	1	NM_147127.5	ENSP00000342144.5
EVC2	ENST00000310917.6	c.784A>G	p.Lys262Glu	missense_variant	Exon 9 of 22	1		ENSP00000311683.2
EVC2	ENST00000475313.5	n.784A>G		non_coding_transcript_exon_variant	Exon 9 of 23	1		ENSP00000431981.1
EVC2	ENST00000509670.1	n.784A>G		non_coding_transcript_exon_variant	Exon 10 of 23	1		ENSP00000423876.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;.
Eigen	Benign	0.077
Eigen_PC	Benign	-0.030
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.066	T;T
Sift4G	Uncertain	0.022	D;D
Polyphen		0.98	D;.
Vest4		0.49
MutPred		0.27		Loss of ubiquitination at K342 (P = 0.0043);.;
MVP		0.84
MPC		0.10
ClinPred		0.90	D
GERP RS		2.6
Varity_R		0.14
gMVP		0.34

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: rs767072839; hg19: chr4-5664955;