rs139991238

Positions:

• chr19-11441305-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001289104.2(PRKCSH):​c.416G>A​(p.Arg139His) variant causes a missense change. The variant allele was found at a frequency of 0.00176 in 1,614,026 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (1 hom.)
• Consequence: PRKCSH NM_001289104.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 4.33

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009291679).
• BP6: Variant 19-11441305-G-A is Benign according to our data. Variant chr19-11441305-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283561.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00126 (192/152266) while in subpopulation NFE AF= 0.00187 (127/68020). AF 95% confidence interval is 0.0016. There are 0 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 192 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKCSH	NM_001289104.2	c.416G>A	p.Arg139His	missense_variant	6/18	ENST00000677123.1	NP_001276033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKCSH	ENST00000677123.1	c.416G>A	p.Arg139His	missense_variant	6/18		NM_001289104.2	ENSP00000503163.1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00155 AC: 389 AN: 251472 Hom.: 0 AF XY: 0.00150 AC XY: 204 AN XY: 135914

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00610

Gnomad NFE exome AF: 0.00209

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00181 AC: 2653 AN: 1461760 Hom.: 1 Cov.: 31 AF XY: 0.00180 AC XY: 1306 AN XY: 727190

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00584

Gnomad4 NFE exome AF: 0.00202

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74438

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00452

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.00180 Hom.: 0

Bravo AF: 0.000979

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00163 AC: 198

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2020	This variant is associated with the following publications: (PMID: 16835903, 22415584) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PRKCSH: BS1, BS2 -

Polycystic liver disease 1 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 22, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.050	.;.;T;T;T;.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.0093	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.0	M;.;.;.;.;M;M
PrimateAI	Benign	0.45	T
Sift4G	Benign	0.12	T;T;D;T;T;T;T
Polyphen		1.0	.;.;.;.;.;.;D
Vest4		0.33
MVP		0.84
ClinPred		0.032	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs139991238; hg19: chr19-11552120;