NM_001289104.2:c.1378A>G

Variant names:

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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCSH	NM_001289104.2 link	c.1378A>G	p.Ile460Val	missense_variant	Exon 16 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.1378A>G	p.Ile460Val	missense_variant	Exon 16 of 18		NM_001289104.2	ENSP00000503163.1		K7ELL7

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

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

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

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PRKCSH: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 11, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic liver disease 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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

.;T;.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.023

.;T;T;T

MetaRNN

Benign

0.0085

T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-0.090

.;.;.;N

PhyloP100

2.7

PrimateAI

Uncertain

0.49

Sift4G

Benign

0.53

T;T;T;T

Polyphen

0.0

.;.;.;B

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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NM_001289104.2:c.1378A>G

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