NM_001289104.2:c.966_968dupGGA

Variant names:

• chr19-11447525-A-AGAG
• rs3217229
• NM_001289104.2:c.966_968dupGGA

Variant summary

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

The NM_001289104.2(PRKCSH):​c.966_968dupGGA​(p.Glu323dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E323E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.042 (141 hom., cov: 0)
  • Exomes 𝑓: 0.037 (135 hom.)
• Consequence: PRKCSH NM_001289104.2 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001289104.2
• BP6: Variant 19-11447525-A-AGAG is Benign according to our data. Variant chr19-11447525-A-AGAG is described in ClinVar as Benign. ClinVar VariationId is 1260325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0419 (6261/149576) while in subpopulation AFR AF = 0.051 (2069/40602). AF 95% confidence interval is 0.0491. There are 141 homozygotes in GnomAd4. There are 3010 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 6261 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289104.2. 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.966_968dupGGA	p.Glu323dup	disruptive_inframe_insertion	Exon 11 of 18	NP_001276033.1
	PRKCSH	NM_001289103.2		c.966_968dupGGA	p.Glu323dup	disruptive_inframe_insertion	Exon 11 of 18	NP_001276032.1
	PRKCSH	NM_001379608.1		c.966_968dupGGA	p.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.966_968dupGGA	p.Glu323dup	disruptive_inframe_insertion	Exon 11 of 18	ENSP00000503163.1
	PRKCSH	ENST00000592741.5	TSL:1	c.966_968dupGGA	p.Glu323dup	disruptive_inframe_insertion	Exon 11 of 18	ENSP00000466134.1
	PRKCSH	ENST00000589838.5	TSL:1	c.966_968dupGGA	p.Glu323dup	disruptive_inframe_insertion	Exon 10 of 17	ENSP00000465461.1

Frequencies

GnomAD3 genomes AF: 0.0419 AC: 6257 AN: 149468 Hom.: 141 Cov.: 0

Gnomad AFR AF: 0.0510

Gnomad AMI AF: 0.0112

Gnomad AMR AF: 0.0355

Gnomad ASJ AF: 0.0416

Gnomad EAS AF: 0.00395

Gnomad SAS AF: 0.00619

Gnomad FIN AF: 0.0548

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0414

Gnomad OTH AF: 0.0483

GnomAD2 exomes AF: 0.0337 AC: 5909 AN: 175324 AF XY: 0.0324

Gnomad AFR exome AF: 0.0520

Gnomad AMR exome AF: 0.0369

Gnomad ASJ exome AF: 0.0398

Gnomad EAS exome AF: 0.00611

Gnomad FIN exome AF: 0.0519

Gnomad NFE exome AF: 0.0363

Gnomad OTH exome AF: 0.0434

GnomAD4 exome AF: 0.0367 AC: 52682 AN: 1433844 Hom.: 135 Cov.: 0 AF XY: 0.0358 AC XY: 25478 AN XY: 712564

African (AFR) AF: 0.0503 AC: 1654 AN: 32870

American (AMR) AF: 0.0302 AC: 1267 AN: 42020

Ashkenazi Jewish (ASJ) AF: 0.0355 AC: 910 AN: 25656

East Asian (EAS) AF: 0.00263 AC: 103 AN: 39096

South Asian (SAS) AF: 0.00884 AC: 743 AN: 84052

European-Finnish (FIN) AF: 0.0494 AC: 2551 AN: 51632

Middle Eastern (MID) AF: 0.0209 AC: 116 AN: 5546

European-Non Finnish (NFE) AF: 0.0395 AC: 43241 AN: 1093652

Other (OTH) AF: 0.0354 AC: 2097 AN: 59320

GnomAD4 genome AF: 0.0419 AC: 6261 AN: 149576 Hom.: 141 Cov.: 0 AF XY: 0.0413 AC XY: 3010 AN XY: 72882

African (AFR) AF: 0.0510 AC: 2069 AN: 40602

American (AMR) AF: 0.0355 AC: 535 AN: 15088

Ashkenazi Jewish (ASJ) AF: 0.0416 AC: 143 AN: 3434

East Asian (EAS) AF: 0.00376 AC: 19 AN: 5054

South Asian (SAS) AF: 0.00620 AC: 29 AN: 4678

European-Finnish (FIN) AF: 0.0548 AC: 557 AN: 10160

Middle Eastern (MID) AF: 0.0411 AC: 12 AN: 292

European-Non Finnish (NFE) AF: 0.0414 AC: 2789 AN: 67326

Other (OTH) AF: 0.0478 AC: 98 AN: 2052

Alfa AF: 0.0245 Hom.: 370

Bravo AF: 0.0420

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (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; COSMIC: COSV52950610; COSMIC: COSV52950610;