Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001289104.2(PRKCSH):c.1378A>G(p.Ile460Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00737 in 1,613,504 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0056 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0076 ( 51 hom. )

Consequence

PRKCSH
NM_001289104.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.70

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00853613).

BP6

Variant 19-11449092-A-G is Benign according to our data. Variant chr19-11449092-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258793.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 = 0.00555 (845/152200) while in subpopulation SAS AF = 0.0131 (63/4822). AF 95% confidence interval is 0.0105. There are 8 homozygotes in GnomAd4. There are 426 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 845 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRKCSH	NM_001289104.2	MANE Select	c.1378A>G	p.Ile460Val	missense	Exon 16 of 18	NP_001276033.1
PRKCSH	NM_001289103.2		c.1378A>G	p.Ile460Val	missense	Exon 16 of 18	NP_001276032.1
PRKCSH	NM_001379608.1		c.1357A>G	p.Ile453Val	missense	Exon 16 of 18	NP_001366537.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRKCSH	ENST00000677123.1	MANE Select	c.1378A>G	p.Ile460Val	missense	Exon 16 of 18	ENSP00000503163.1
PRKCSH	ENST00000592741.5	TSL:1	c.1378A>G	p.Ile460Val	missense	Exon 16 of 18	ENSP00000466134.1
PRKCSH	ENST00000589838.5	TSL:1	c.1357A>G	p.Ile453Val	missense	Exon 15 of 17	ENSP00000465461.1

Frequencies

GnomAD3 genomes

AF:

0.00552

AC:

840

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.0429

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00792

Gnomad SAS

AF:

0.0131

Gnomad FIN

AF:

0.00754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00774

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00635

AC:

1592

AN:

250832

AF XY:

0.00702

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00805

Gnomad FIN exome

AF:

0.00657

Gnomad NFE exome

AF:

0.00725

Gnomad OTH exome

AF:

0.00604

GnomAD4 exome

AF:

0.00756

AC:

11052

AN:

1461304

Hom.:

Cov.:

AF XY:

0.00779

AC XY:

5663

AN XY:

726956

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

33480

American (AMR)

AF:

0.00148

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00411

AC:

163

AN:

39700

South Asian (SAS)

AF:

0.0129

AC:

1117

AN:

86258

European-Finnish (FIN)

AF:

0.00537

AC:

284

AN:

52844

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00806

AC:

8967

AN:

1112002

Other (OTH)

AF:

0.00618

AC:

373

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

775

1550

2325

3100

3875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

360

720

1080

1440

1800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00555

AC:

845

AN:

152200

Hom.:

Cov.:

AF XY:

0.00573

AC XY:

426

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

41530

American (AMR)

AF:

0.00255

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00794

AC:

AN:

5166

South Asian (SAS)

AF:

0.0131

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00754

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00774

AC:

526

AN:

67986

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00663

Hom.:

Bravo

AF:

0.00492

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00744

AC:

ExAC

AF:

0.00641

AC:

778

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00567

EpiControl

AF:

0.00741

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (1)

Polycystic liver disease 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.15

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.023

MetaRNN

Benign

0.0085

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-0.090

PhyloP100

2.7

PrimateAI

Uncertain

0.49

Sift4G

Benign

0.53

Polyphen

0.0

Vest4

0.16

MVP

0.28

ClinPred

0.0037

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

gMVP

0.51

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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rs34351170

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over