rs909612975
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PM2PP3_ModeratePP5_Very_Strong
The NM_153717.3(EVC):c.1777-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000645 in 1,551,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000057 ( 0 hom. )
Consequence
EVC
NM_153717.3 splice_acceptor
NM_153717.3 splice_acceptor
Scores
3
2
2
Splicing: ADA: 0.9999
1
Clinical Significance
Conservation
PhyloP100: 4.68
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]
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 4-5793606-A-G is Pathogenic according to our data. Variant chr4-5793606-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5793606-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EVC | NM_153717.3 | c.1777-2A>G | splice_acceptor_variant | ENST00000264956.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EVC | ENST00000264956.11 | c.1777-2A>G | splice_acceptor_variant | 1 | NM_153717.3 | P1 | |||
EVC | ENST00000506240.1 | n.93A>G | non_coding_transcript_exon_variant | 1/2 | 3 | ||||
CRMP1 | ENST00000506216.5 | n.1647+31888T>C | intron_variant, non_coding_transcript_variant | 5 | |||||
EVC | ENST00000515113.1 | upstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000640 AC: 1AN: 156284Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 82290
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GnomAD4 exome AF: 0.00000572 AC: 8AN: 1399198Hom.: 0 Cov.: 29 AF XY: 0.00000724 AC XY: 5AN XY: 690198
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ellis-van Creveld syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 15, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 27, 2020 | - - |
Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 03, 2023 | This sequence change affects an acceptor splice site in intron 12 of the EVC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EVC are known to be pathogenic (PMID: 23220543). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with Ellis-van Creveld syndrome (PMID: 17024374, 23220543). This variant is also known as IVS12-2A > G. ClinVar contains an entry for this variant (Variation ID: 551792). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | EVC: PVS1, PM2 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Benign
D
MutationTaster
Benign
D;D
GERP RS
Splicing
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dbscSNV1_ADA
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -3
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at