rs781763471
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Moderate
The NM_006929.5(SKIC2):c.2341-2A>C variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000103 in 1,460,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
SKIC2
NM_006929.5 splice_acceptor
NM_006929.5 splice_acceptor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.42
Genes affected
SKIC2 (HGNC:10898): (SKI2 subunit of superkiller complex) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which is a human homologue of yeast SKI2 and may be involved in antiviral activity by blocking translation of poly(A) deficient mRNAs. This gene is located in the class III region of the major histocompatibility complex. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.0061035375 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.7, offset of 12, new splice context is: cacccacggcccatgaacAGgcc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 6-31967002-A-C is Pathogenic according to our data. Variant chr6-31967002-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2803130.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SKIC2 | NM_006929.5 | c.2341-2A>C | splice_acceptor_variant | ENST00000375394.7 | |||
SKIC2 | XM_011514815.4 | c.2341-2A>C | splice_acceptor_variant | ||||
SKIC2 | XM_047419259.1 | c.2341-2A>C | splice_acceptor_variant | ||||
SKIC2 | XM_047419260.1 | c.2341-2A>C | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SKIC2 | ENST00000375394.7 | c.2341-2A>C | splice_acceptor_variant | 1 | NM_006929.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1460732Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 726682
GnomAD4 exome
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AC:
15
AN:
1460732
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Cov.:
32
AF XY:
AC XY:
8
AN XY:
726682
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 18, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individual(s) with trichohepatoenteric syndrome (PMID: 29527791). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 19 of the SKIV2L 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 SKIV2L are known to be pathogenic (PMID: 22444670). - |
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
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 14
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at