chr19-11449074-A-G

Position:

• chr19-11449074-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001289104.2(PRKCSH):​c.1362-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,188 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRKCSH NM_001289104.2 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.15

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]

PRKCSH (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) 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
• PP5: Variant 19-11449074-A-G is Pathogenic according to our data. Variant chr19-11449074-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13238.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-11449074-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKCSH	NM_001289104.2	c.1362-2A>G		splice_acceptor_variant, intron_variant		ENST00000677123.1	NP_001276033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKCSH	ENST00000677123.1	c.1362-2A>G		splice_acceptor_variant, intron_variant			NM_001289104.2	ENSP00000503163.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461188 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726912

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Polycystic liver disease 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Dec 17, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Benign	0.80
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.94	D
GERP RS		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.72
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555728968; hg19: chr19-11559889;