19-11436155-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001289104.2(PRKCSH):c.38G>C(p.Trp13Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000904 in 1,603,430 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W13R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: PRKCSH NM_001289104.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.270

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026471555).
• BP6: Variant 19-11436155-G-C is Benign according to our data. Variant chr19-11436155-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1529457.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKCSH	NM_001289104.2	c.38G>C	p.Trp13Ser	missense_variant	2/18	ENST00000677123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKCSH	ENST00000677123.1	c.38G>C	p.Trp13Ser	missense_variant	2/18		NM_001289104.2	A2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000128 AC: 29 AN: 227330 Hom.: 0 AF XY: 0.000145 AC XY: 18 AN XY: 123840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000920

Gnomad ASJ exome AF: 0.00197

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000495

Gnomad OTH exome AF: 0.000350

GnomAD4 exome AF: 0.0000882 AC: 128 AN: 1451142 Hom.: 0 Cov.: 31 AF XY: 0.0000901 AC XY: 65 AN XY: 721666

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000923

Gnomad4 ASJ exome AF: 0.00204

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000586

Gnomad4 OTH exome AF: 0.0000999

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74452

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000290 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000742 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2023

The c.38G>C (p.W13S) alteration is located in exon 2 (coding exon 1) of the PRKCSH gene. This alteration results from a G to C substitution at nucleotide position 38, causing the tryptophan (W) at amino acid position 13 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	16
Dann	Benign	0.70
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.52	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.026	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.99	N;.;.;.;.;.;.;N;N
MutationTaster	Benign	0.90	D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
Sift4G	Benign	0.71	T;T;T;D;T;T;T;T;T
Polyphen		0.0040	.;.;.;.;.;.;.;.;B
Vest4		0.32
MutPred		0.62		Loss of catalytic residue at W13 (P = 0.0055);Loss of catalytic residue at W13 (P = 0.0055);Loss of catalytic residue at W13 (P = 0.0055);Loss of catalytic residue at W13 (P = 0.0055);Loss of catalytic residue at W13 (P = 0.0055);Loss of catalytic residue at W13 (P = 0.0055);Loss of catalytic residue at W13 (P = 0.0055);Loss of catalytic residue at W13 (P = 0.0055);Loss of catalytic residue at W13 (P = 0.0055);
MVP		0.48
ClinPred		0.025	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.078
gMVP		0.27

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: rs545088289; hg19: chr19-11546976;