19-11449130-T-A

Variant names:

• chr19-11449130-T-A
• NM_001289104.2:c.1416T>A
• PRKCSH p.Tyr472*

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP3

The NM_001289104.2(PRKCSH):​c.1416T>A​(p.Tyr472*) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKCSH NM_001289104.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.694
• 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: Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen

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
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCSH	NM_001289104.2	MANE Select	c.1416T>A	p.Tyr472*	stop_gained	Exon 16 of 18	NP_001276033.1	K7ELL7
	PRKCSH	NM_001289103.2		c.1416T>A	p.Tyr472*	stop_gained	Exon 16 of 18	NP_001276032.1	K7ELL7
	PRKCSH	NM_001379608.1		c.1395T>A	p.Tyr465*	stop_gained	Exon 16 of 18	NP_001366537.1	P14314-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCSH	ENST00000677123.1	MANE Select	c.1416T>A	p.Tyr472*	stop_gained	Exon 16 of 18	ENSP00000503163.1	K7ELL7
	PRKCSH	ENST00000592741.5	TSL:1	c.1416T>A	p.Tyr472*	stop_gained	Exon 16 of 18	ENSP00000466134.1	K7ELL7
	PRKCSH	ENST00000589838.5	TSL:1	c.1395T>A	p.Tyr465*	stop_gained	Exon 15 of 17	ENSP00000465461.1	P14314-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	36
DANN	Benign	0.96
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.39	N
PhyloP100		-0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.60		Position offset: -4

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-11559945;