19-11447525-AGAGGAGGAGGAGGAGGAG-AGAGGAG

Variant names:

• chr19-11447525-AGAGGAGGAGGAG-A
• rs3217229
• NM_001289104.2:c.957_968delGGAGGAGGAGGA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001289103.2(PRKCSH):​c.957_968delGGAGGAGGAGGA​(p.Glu320_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 0.000161 in 1,583,918 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: PRKCSH NM_001289103.2 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001289103.2
• BP6: Variant 19-11447525-AGAGGAGGAGGAG-A is Benign according to our data. Variant chr19-11447525-AGAGGAGGAGGAG-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2051254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000166 (238/1434292) while in subpopulation EAS AF = 0.00228 (89/39096). AF 95% confidence interval is 0.00189. There are 1 homozygotes in GnomAdExome4. There are 121 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High AC in GnomAd4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289103.2. 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.957_968delGGAGGAGGAGGA	p.Glu320_Glu323del	disruptive_inframe_deletion	Exon 11 of 18	NP_001276033.1
	PRKCSH	NM_001289103.2		c.957_968delGGAGGAGGAGGA	p.Glu320_Glu323del	disruptive_inframe_deletion	Exon 11 of 18	NP_001276032.1
	PRKCSH	NM_001379608.1		c.957_968delGGAGGAGGAGGA	p.Glu320_Glu323del	disruptive_inframe_deletion	Exon 11 of 18	NP_001366537.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCSH	ENST00000677123.1	MANE Select	c.957_968delGGAGGAGGAGGA	p.Glu320_Glu323del	disruptive_inframe_deletion	Exon 11 of 18	ENSP00000503163.1
	PRKCSH	ENST00000592741.5	TSL:1	c.957_968delGGAGGAGGAGGA	p.Glu320_Glu323del	disruptive_inframe_deletion	Exon 11 of 18	ENSP00000466134.1
	PRKCSH	ENST00000589838.5	TSL:1	c.957_968delGGAGGAGGAGGA	p.Glu320_Glu323del	disruptive_inframe_deletion	Exon 10 of 17	ENSP00000465461.1

Frequencies

GnomAD3 genomes AF: 0.000114 AC: 17 AN: 149518 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000741

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000395

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000166 AC: 238 AN: 1434292 Hom.: 1 AF XY: 0.000170 AC XY: 121 AN XY: 712772

African (AFR) AF: 0.0000912 AC: 3 AN: 32884

American (AMR) AF: 0.0000952 AC: 4 AN: 42036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25668

East Asian (EAS) AF: 0.00228 AC: 89 AN: 39096

South Asian (SAS) AF: 0.000178 AC: 15 AN: 84050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51680

Middle Eastern (MID) AF: 0.000902 AC: 5 AN: 5546

European-Non Finnish (NFE) AF: 0.0000987 AC: 108 AN: 1093992

Other (OTH) AF: 0.000236 AC: 14 AN: 59340

GnomAD4 genome AF: 0.000114 AC: 17 AN: 149626 Hom.: 0 Cov.: 0 AF XY: 0.0000686 AC XY: 5 AN XY: 72902

African (AFR) AF: 0.0000739 AC: 3 AN: 40622

American (AMR) AF: 0.0000663 AC: 1 AN: 15092

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

East Asian (EAS) AF: 0.000396 AC: 2 AN: 5054

South Asian (SAS) AF: 0.00 AC: 0 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: 0.000163 AC: 11 AN: 67348

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

Alfa AF: 0.000108 Hom.: 370

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Polycystic liver disease 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=148/52	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;