19-11447525-AGAGGAGGAGGAGGAGGAG-AGAG

Variant names:

• chr19-11447525-AGAGGAGGAGGAGGAG-A
• rs3217229
• NM_001289104.2:c.954_968delGGAGGAGGAGGAGGA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_001289104.2(PRKCSH):​c.954_968delGGAGGAGGAGGAGGA​(p.Glu319_Glu323del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,583,934 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: PRKCSH NM_001289104.2 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27
• Publications: 11 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: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001289104.2
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCSH	NM_001289104.2	c.954_968delGGAGGAGGAGGAGGA	p.Glu319_Glu323del	disruptive_inframe_deletion	Exon 11 of 18	ENST00000677123.1	NP_001276033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCSH	ENST00000677123.1	c.954_968delGGAGGAGGAGGAGGA	p.Glu319_Glu323del	disruptive_inframe_deletion	Exon 11 of 18		NM_001289104.2	ENSP00000503163.1

Frequencies

GnomAD3 genomes AF: 0.000161 AC: 24 AN: 149516 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000494

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000297

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000151 AC: 217 AN: 1434310 Hom.: 0 AF XY: 0.000146 AC XY: 104 AN XY: 712786

African (AFR) AF: 0.0000304 AC: 1 AN: 32884

American (AMR) AF: 0.000119 AC: 5 AN: 42036

Ashkenazi Jewish (ASJ) AF: 0.0000390 AC: 1 AN: 25668

East Asian (EAS) AF: 0.00 AC: 0 AN: 39096

South Asian (SAS) AF: 0.0000238 AC: 2 AN: 84056

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5546

European-Non Finnish (NFE) AF: 0.000179 AC: 196 AN: 1094004

Other (OTH) AF: 0.000185 AC: 11 AN: 59340

GnomAD4 genome AF: 0.000160 AC: 24 AN: 149624 Hom.: 0 Cov.: 0 AF XY: 0.000165 AC XY: 12 AN XY: 72900

African (AFR) AF: 0.0000492 AC: 2 AN: 40622

American (AMR) AF: 0.0000663 AC: 1 AN: 15090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5054

South Asian (SAS) AF: 0.000214 AC: 1 AN: 4678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000297 AC: 20 AN: 67348

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.00 Hom.: 370

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.954_968del, results in the deletion of 5 amino acid(s) of the PRKCSH protein (p.Glu321_Glu325del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRKCSH-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=144/56	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs3217229; hg19: chr19-11558340;