rs186375

Positions:

• chr19-11447425-T-C
• chr19-11447425-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001289104.2(PRKCSH):​c.850-14T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,613,382 control chromosomes in the GnomAD database, including 791,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (75015 hom., cov: 32)
  • Exomes 𝑓: 0.99 (716104 hom.)
• Consequence: PRKCSH NM_001289104.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.01

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=-0.92).
• BP6: Variant 19-11447425-T-C is Benign according to our data. Variant chr19-11447425-T-C is described in ClinVar as [Benign]. Clinvar id is 94078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11447425-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKCSH	NM_001289104.2	c.850-14T>C		splice_polypyrimidine_tract_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.850-14T>C		splice_polypyrimidine_tract_variant, intron_variant			NM_001289104.2	ENSP00000503163	A2

Frequencies

GnomAD3 genomes AF: 0.993 AC: 151014 AN: 152134 Hom.: 74956 Cov.: 32

Gnomad AFR AF: 0.998

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.997

Gnomad ASJ AF: 0.988

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.993

Gnomad FIN AF: 0.984

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.989

Gnomad OTH AF: 0.994

GnomAD3 exomes AF: 0.992 AC: 246342 AN: 248298 Hom.: 122213 AF XY: 0.992 AC XY: 133382 AN XY: 134490

Gnomad AFR exome AF: 0.999

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 0.991

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.993

Gnomad FIN exome AF: 0.985

Gnomad NFE exome AF: 0.990

Gnomad OTH exome AF: 0.994

GnomAD4 exome AF: 0.990 AC: 1446577 AN: 1461130 Hom.: 716104 Cov.: 48 AF XY: 0.990 AC XY: 719644 AN XY: 726862

Gnomad4 AFR exome AF: 0.998

Gnomad4 AMR exome AF: 0.997

Gnomad4 ASJ exome AF: 0.992

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.993

Gnomad4 FIN exome AF: 0.985

Gnomad4 NFE exome AF: 0.989

Gnomad4 OTH exome AF: 0.992

GnomAD4 genome AF: 0.993 AC: 151132 AN: 152252 Hom.: 75015 Cov.: 32 AF XY: 0.992 AC XY: 73864 AN XY: 74424

Gnomad4 AFR AF: 0.998

Gnomad4 AMR AF: 0.997

Gnomad4 ASJ AF: 0.988

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.993

Gnomad4 FIN AF: 0.984

Gnomad4 NFE AF: 0.989

Gnomad4 OTH AF: 0.994

Alfa AF: 0.991 Hom.: 13720

Bravo AF: 0.994

Asia WGS AF: 0.997 AC: 3465 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Polycystic liver disease 1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.66
DANN	Benign	0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs186375; hg19: chr19-11558240;