rs757957327
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PVS1PP3PP5BS2_Supporting
The NM_001289104.2(PRKCSH):c.1461+2_1461+3del variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,652 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
PRKCSH
NM_001289104.2 splice_donor
NM_001289104.2 splice_donor
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.79
Genes affected
PRKCSH (HGNC:9411): (PRKCSH beta subunit of glucosidase II) This gene encodes the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum. The encoded protein is an acidic phosphoprotein known to be a substrate for protein kinase C. Mutations in this gene have been associated with the autosomal dominant polycystic liver disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.3, offset of -49, new splice context is: gaaGTatga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PP3
Multiple lines of computational evidence support a deleterious effect 2: max_spliceai, phyloP100way_vertebrate [when was below the threshold]
PP5
Variant 19-11449175-CGT-C is Pathogenic according to our data. Variant chr19-11449175-CGT-C is described in ClinVar as [Pathogenic]. Clinvar id is 13240.Status of the report is no_assertion_criteria_provided, 0 stars.
BS2
High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRKCSH | NM_001289104.2 | c.1461+2_1461+3del | splice_donor_variant | ENST00000677123.1 | NP_001276033.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRKCSH | ENST00000677123.1 | c.1461+2_1461+3del | splice_donor_variant | NM_001289104.2 | ENSP00000503163 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152240Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000600 AC: 15AN: 250128Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135474
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GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461412Hom.: 0 AF XY: 0.0000179 AC XY: 13AN XY: 727058
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GnomAD4 genome AF: 0.0000328 AC: 5AN: 152240Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74374
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Polycystic liver disease 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2003 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -49
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at