rs6446393

Positions:

• chr4-5741782-C-G
• chr4-5741782-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_153717.3(EVC):​c.769C>G​(p.Leu257Val) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L257Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00

Genes affected

EVC (HGNC:3497): (EvC ciliary complex subunit 1) This gene encodes a protein containing a leucine zipper and a transmembrane domain. This gene has been implicated in both Ellis-van Creveld syndrome (EvC) and Weyers acrodental dysostosis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-5741783-T-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.21433458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC	NM_153717.3	c.769C>G	p.Leu257Val	missense_variant	6/21	ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11	c.769C>G	p.Leu257Val	missense_variant	6/21	1	NM_153717.3	ENSP00000264956.6
EVC	ENST00000509451.1	c.769C>G	p.Leu257Val	missense_variant	6/12	1		ENSP00000426774.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.076
Sift	Benign	0.052	T;T
Sift4G	Benign	0.087	T;T
Polyphen		0.87	P;.
Vest4		0.45
MutPred		0.39		Gain of glycosylation at Y258 (P = 0.0051);Gain of glycosylation at Y258 (P = 0.0051);
MVP		0.45
ClinPred		0.31	T
GERP RS		1.1
Varity_R		0.064
gMVP		0.19

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: rs6446393; hg19: chr4-5743509;