19-11447525-AGAGGAGGAG-A

Variant names:

• chr19-11447525-AGAGGAGGAG-A
• rs3217229
• NM_001289104.2:c.960_968delGGAGGAGGA

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.960_968delGGAGGAGGA​(p.Glu321_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 0.000478 in 1,578,224 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: PRKCSH NM_001289103.2 disruptive_inframe_deletion
• Clinical Significance: Benign/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-AGAGGAGGAG-A is Benign according to our data. Variant chr19-11447525-AGAGGAGGAG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 713728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000408 (61/149622) while in subpopulation SAS AF = 0.00214 (10/4678). AF 95% confidence interval is 0.00116. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 61 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_968delGGAGGAGGA	p.Glu321_Glu323del	disruptive_inframe_deletion	Exon 11 of 18	NP_001276033.1
	PRKCSH	NM_001289103.2		c.960_968delGGAGGAGGA	p.Glu321_Glu323del	disruptive_inframe_deletion	Exon 11 of 18	NP_001276032.1
	PRKCSH	NM_001379608.1		c.960_968delGGAGGAGGA	p.Glu321_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.960_968delGGAGGAGGA	p.Glu321_Glu323del	disruptive_inframe_deletion	Exon 11 of 18	ENSP00000503163.1
	PRKCSH	ENST00000592741.5	TSL:1	c.960_968delGGAGGAGGA	p.Glu321_Glu323del	disruptive_inframe_deletion	Exon 11 of 18	ENSP00000466134.1
	PRKCSH	ENST00000589838.5	TSL:1	c.960_968delGGAGGAGGA	p.Glu321_Glu323del	disruptive_inframe_deletion	Exon 10 of 17	ENSP00000465461.1

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 61 AN: 149514 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000199

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00158

Gnomad SAS AF: 0.00213

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000386

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00117 AC: 205 AN: 175324 AF XY: 0.00127

Gnomad AFR exome AF: 0.000590

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.000913

Gnomad EAS exome AF: 0.00256

Gnomad FIN exome AF: 0.000315

Gnomad NFE exome AF: 0.000940

Gnomad OTH exome AF: 0.00161

GnomAD4 exome AF: 0.000485 AC: 693 AN: 1428602 Hom.: 0 AF XY: 0.000497 AC XY: 353 AN XY: 709860

African (AFR) AF: 0.000335 AC: 11 AN: 32844

American (AMR) AF: 0.000931 AC: 39 AN: 41912

Ashkenazi Jewish (ASJ) AF: 0.000668 AC: 17 AN: 25456

East Asian (EAS) AF: 0.00133 AC: 52 AN: 39094

South Asian (SAS) AF: 0.00135 AC: 113 AN: 83886

European-Finnish (FIN) AF: 0.0000969 AC: 5 AN: 51596

Middle Eastern (MID) AF: 0.000543 AC: 3 AN: 5526

European-Non Finnish (NFE) AF: 0.000381 AC: 415 AN: 1089212

Other (OTH) AF: 0.000643 AC: 38 AN: 59076

GnomAD4 genome AF: 0.000408 AC: 61 AN: 149622 Hom.: 0 Cov.: 0 AF XY: 0.000480 AC XY: 35 AN XY: 72898

African (AFR) AF: 0.000345 AC: 14 AN: 40622

American (AMR) AF: 0.000199 AC: 3 AN: 15092

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

East Asian (EAS) AF: 0.00158 AC: 8 AN: 5054

South Asian (SAS) AF: 0.00214 AC: 10 AN: 4678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10160

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

European-Non Finnish (NFE) AF: 0.000386 AC: 26 AN: 67346

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

Alfa AF: 0.00183 Hom.: 370

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=196/4	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;