rs121918520

Variant names:

• chr19-11448917-C-A
• rs121918520
• NM_001289104.2:c.1290C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11448917-C-A
• chr19-11448917-C-G
• chr19-11448917-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001289104.2(PRKCSH):​c.1290C>A​(p.Tyr430*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Y430Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKCSH NM_001289104.2 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -1.05
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• polycystic liver disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11448917-C-A is Pathogenic according to our data. Variant chr19-11448917-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1255531.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289104.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCSH	NM_001289104.2	MANE Select	c.1290C>A	p.Tyr430*	stop_gained	Exon 15 of 18	NP_001276033.1
	PRKCSH	NM_001289103.2		c.1290C>A	p.Tyr430*	stop_gained	Exon 15 of 18	NP_001276032.1
	PRKCSH	NM_001379608.1		c.1269C>A	p.Tyr423*	stop_gained	Exon 15 of 18	NP_001366537.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCSH	ENST00000677123.1	MANE Select	c.1290C>A	p.Tyr430*	stop_gained	Exon 15 of 18	ENSP00000503163.1
	PRKCSH	ENST00000592741.5	TSL:1	c.1290C>A	p.Tyr430*	stop_gained	Exon 15 of 18	ENSP00000466134.1
	PRKCSH	ENST00000589838.5	TSL:1	c.1269C>A	p.Tyr423*	stop_gained	Exon 14 of 17	ENSP00000465461.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant polycystic liver disease Pathogenic:1

Sep 01, 2021

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Benign	0.95
Eigen	Benign	-0.63
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.27	N
PhyloP100		-1.0
Vest4		0.79
GERP RS		-7.3
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 25

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

Other links and lift over

dbSNP: rs121918520; hg19: chr19-11559732;