rs150798392

chr19-11448643-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001289104.2(PRKCSH):c.1286+14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00738 in 1,612,458 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (51 hom.)
• Consequence: PRKCSH NM_001289104.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.07

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-11448643-A-G is Benign according to our data. Variant chr19-11448643-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 258791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11448643-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00556 (847/152342) while in subpopulation SAS AF= 0.0131 (63/4826). AF 95% confidence interval is 0.0105. There are 9 homozygotes in gnomad4. There are 428 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 842 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKCSH	NM_001289104.2	c.1286+14A>G		intron_variant		ENST00000677123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKCSH	ENST00000677123.1	c.1286+14A>G		intron_variant			NM_001289104.2	A2

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 842 AN: 152224 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00789

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.00753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00773

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00636 AC: 1597 AN: 250976 Hom.: 6 AF XY: 0.00704 AC XY: 956 AN XY: 135772

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00816

Gnomad SAS exome AF: 0.0121

Gnomad FIN exome AF: 0.00649

Gnomad NFE exome AF: 0.00727

Gnomad OTH exome AF: 0.00622

GnomAD4 exome AF: 0.00757 AC: 11047 AN: 1460116 Hom.: 51 Cov.: 31 AF XY: 0.00779 AC XY: 5659 AN XY: 726526

Gnomad4 AFR exome AF: 0.00150

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00421

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.00532

Gnomad4 NFE exome AF: 0.00807

Gnomad4 OTH exome AF: 0.00615

GnomAD4 genome AF: 0.00556 AC: 847 AN: 152342 Hom.: 9 Cov.: 32 AF XY: 0.00575 AC XY: 428 AN XY: 74490

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00791

Gnomad4 SAS AF: 0.0131

Gnomad4 FIN AF: 0.00753

Gnomad4 NFE AF: 0.00773

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00667 Hom.: 0

Bravo AF: 0.00493

Asia WGS AF: 0.0100 AC: 35 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic liver disease 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	3.9
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs150798392; hg19: chr19-11559458; COSMIC: COSV52953620; COSMIC: COSV52953620;