dbSNP rs1373632260: EVC:p.Leu623Gln (chr4-5793699-T-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The NM_153717.3(EVC):c.1868T>A(p.Leu623Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,398,294 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 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. L623P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

EVC
NM_153717.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.02

Variant links:

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]

EVC links:

CRMP1 (HGNC:2365): (collapsin response mediator protein 1) This gene encodes a member of a family of cytosolic phosphoproteins expressed exclusively in the nervous system. The encoded protein is thought to be a part of the semaphorin signal transduction pathway implicated in semaphorin-induced growth cone collapse during neural development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

CRMP1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-5793699-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC	NM_153717.3 link	c.1868T>A	p.Leu623Gln	missense_variant	Exon 13 of 21	ENST00000264956.11	NP_714928.1	P57679

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EVC	ENST00000264956.11 link	c.1868T>A	p.Leu623Gln	missense_variant	Exon 13 of 21	1	NM_153717.3	ENSP00000264956.6	P57679
EVC	ENST00000506240.1 link	n.186T>A		non_coding_transcript_exon_variant	Exon 1 of 2	3
EVC	ENST00000515113.1 link	n.92T>A		non_coding_transcript_exon_variant	Exon 1 of 4	5
CRMP1	ENST00000506216.5 link	n.1647+31795A>T		intron_variant	Intron 12 of 12	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1398294

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689718

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.27e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

0.0015

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.11

Eigen

Benign

0.15

Eigen_PC

Benign

-0.0043

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.79

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.70

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.6

REVEL

Benign

0.23

Sift

Benign

0.20

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.58

MutPred

0.45

Gain of glycosylation at T627 (P = 0.0064);

MVP

0.67

ClinPred

0.86

GERP RS

5.2

Varity_R

0.23

gMVP

0.29

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over