19-11447525-AGAGGAGGAGGAGGAGGAG-AGAGGAGGAGGAGGAGGAGGAGGAG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BS1_SupportingBS2

The NM_001289104.2(PRKCSH):c.963_968dupGGAGGA(p.Glu322_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 0.00074 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

PRKCSH
NM_001289104.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.52

Publications

11 publications found

Variant links:

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

PRKCSH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001289104.2

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000742 (111/149626) while in subpopulation AFR AF = 0.00214 (87/40622). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 57 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 111 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCSH	NM_001289104.2 link	c.963_968dupGGAGGA	p.Glu322_Glu323dup	disruptive_inframe_insertion	Exon 11 of 18	ENST00000677123.1	NP_001276033.1	K7ELL7B4DJQ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCSH	ENST00000677123.1 link	c.963_968dupGGAGGA	p.Glu322_Glu323dup	disruptive_inframe_insertion	Exon 11 of 18		NM_001289104.2	ENSP00000503163.1		K7ELL7

Frequencies

GnomAD3 genomes

AF:

0.000742

AC:

111

AN:

149518

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000398

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000395

Gnomad SAS

AF:

0.00107

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000163

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000308

AC:

AN:

175324

AF XY:

0.000220

show subpopulations

Gnomad AFR exome

AF:

0.00147

Gnomad AMR exome

AF:

0.000335

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000496

Gnomad FIN exome

AF:

0.000252

Gnomad NFE exome

AF:

0.000163

Gnomad OTH exome

AF:

0.000230

GnomAD4 exome

AF:

0.000229

AC:

328

AN:

1434296

Hom.:

Cov.:

AF XY:

0.000222

AC XY:

158

AN XY:

712774

show subpopulations

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

African (AFR)

AF:

0.00195

AC:

AN:

32884

American (AMR)

AF:

0.000285

AC:

AN:

42036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25668

East Asian (EAS)

AF:

0.000102

AC:

AN:

39096

South Asian (SAS)

AF:

0.000321

AC:

AN:

84050

European-Finnish (FIN)

AF:

0.000174

AC:

AN:

51680

Middle Eastern (MID)

AF:

0.000361

AC:

AN:

5546

European-Non Finnish (NFE)

AF:

0.000178

AC:

195

AN:

1093996

Other (OTH)

AF:

0.000253

AC:

AN:

59340

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.397

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000742

AC:

111

AN:

149626

Hom.:

Cov.:

AF XY:

0.000782

AC XY:

AN XY:

72902

show subpopulations

African (AFR)

AF:

0.00214

AC:

AN:

40622

American (AMR)

AF:

0.000398

AC:

AN:

15092

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.000396

AC:

AN:

5054

South Asian (SAS)

AF:

0.00107

AC:

AN:

4678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000163

AC:

AN:

67348

Other (OTH)

AF:

0.00

AC:

AN:

2052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000108

Hom.:

370

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.963_968dup, results in the insertion of 2 amino acid(s) of the PRKCSH protein (p.Glu324_Glu325dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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

2.5

Mutation Taster

=75/25

polymorphism

(source)

Splicing

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

Publications

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19-11447525-AGAGGAGGAGGAGGAGGAG-AGAGGAGGAGGAGGAGGAGGAGGAG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over