19-11447525-AGAGGAGGAGGAGGAGGAG-AGAGGAGGAGGAGGAGGAGGAGGAGGAG

Variant names:

• chr19-11447525-A-AGAGGAGGAG
• rs3217229
• NM_001289104.2:c.960_968dupGGAGGAGGA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BS1_Supporting BS2

The NM_001289103.2(PRKCSH):​c.960_968dupGGAGGAGGA​(p.Glu321_Glu323dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E323E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: PRKCSH NM_001289103.2 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52
• 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 -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001289103.2
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000655 (98/149626) while in subpopulation NFE AF = 0.000965 (65/67348). AF 95% confidence interval is 0.000776. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 98 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.960_968dupGGAGGAGGA	p.Glu321_Glu323dup	disruptive_inframe_insertion	Exon 11 of 18	NP_001276033.1
	PRKCSH	NM_001289103.2		c.960_968dupGGAGGAGGA	p.Glu321_Glu323dup	disruptive_inframe_insertion	Exon 11 of 18	NP_001276032.1
	PRKCSH	NM_001379608.1		c.960_968dupGGAGGAGGA	p.Glu321_Glu323dup	disruptive_inframe_insertion	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.960_968dupGGAGGAGGA	p.Glu321_Glu323dup	disruptive_inframe_insertion	Exon 11 of 18	ENSP00000503163.1
	PRKCSH	ENST00000592741.5	TSL:1	c.960_968dupGGAGGAGGA	p.Glu321_Glu323dup	disruptive_inframe_insertion	Exon 11 of 18	ENSP00000466134.1
	PRKCSH	ENST00000589838.5	TSL:1	c.960_968dupGGAGGAGGA	p.Glu321_Glu323dup	disruptive_inframe_insertion	Exon 10 of 17	ENSP00000465461.1

Frequencies

GnomAD3 genomes AF: 0.000655 AC: 98 AN: 149518 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000663

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000886

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000965

Gnomad OTH AF: 0.00246

GnomAD2 exomes AF: 0.000473 AC: 83 AN: 175324 AF XY: 0.000493

Gnomad AFR exome AF: 0.0000983

Gnomad AMR exome AF: 0.000585

Gnomad ASJ exome AF: 0.000522

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000441

Gnomad NFE exome AF: 0.000652

Gnomad OTH exome AF: 0.000690

GnomAD4 exome AF: 0.000679 AC: 974 AN: 1434282 Hom.: 0 Cov.: 0 AF XY: 0.000682 AC XY: 486 AN XY: 712774

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.000571 AC: 24 AN: 42036

Ashkenazi Jewish (ASJ) AF: 0.000468 AC: 12 AN: 25668

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

South Asian (SAS) AF: 0.000131 AC: 11 AN: 84056

European-Finnish (FIN) AF: 0.000813 AC: 42 AN: 51676

Middle Eastern (MID) AF: 0.000361 AC: 2 AN: 5544

European-Non Finnish (NFE) AF: 0.000774 AC: 847 AN: 1093982

Other (OTH) AF: 0.000556 AC: 33 AN: 59340

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000655 AC: 98 AN: 149626 Hom.: 0 Cov.: 0 AF XY: 0.000604 AC XY: 44 AN XY: 72902

African (AFR) AF: 0.000148 AC: 6 AN: 40622

American (AMR) AF: 0.000663 AC: 10 AN: 15092

Ashkenazi Jewish (ASJ) AF: 0.000291 AC: 1 AN: 3436

East Asian (EAS) AF: 0.000198 AC: 1 AN: 5054

South Asian (SAS) AF: 0.00 AC: 0 AN: 4678

European-Finnish (FIN) AF: 0.000886 AC: 9 AN: 10162

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000965 AC: 65 AN: 67348

Other (OTH) AF: 0.00244 AC: 5 AN: 2052

Alfa AF: 0.000485 Hom.: 370

Bravo AF: 0.000548

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=75/25	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;