19-11436184-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001289104.2(PRKCSH):c.67G>C(p.Val23Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKCSH NM_001289104.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.36

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKCSH	NM_001289104.2	c.67G>C	p.Val23Leu	missense_variant	2/18	ENST00000677123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKCSH	ENST00000677123.1	c.67G>C	p.Val23Leu	missense_variant	2/18		NM_001289104.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.67G>C (p.V23L) 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 67, causing the valine (V) at amino acid position 23 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
Sift4G	Uncertain	0.021	D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;.;.;.;D
Vest4		0.77
MutPred		0.31		Loss of methylation at K18 (P = 0.0839);Loss of methylation at K18 (P = 0.0839);Loss of methylation at K18 (P = 0.0839);Loss of methylation at K18 (P = 0.0839);Loss of methylation at K18 (P = 0.0839);Loss of methylation at K18 (P = 0.0839);Loss of methylation at K18 (P = 0.0839);Loss of methylation at K18 (P = 0.0839);Loss of methylation at K18 (P = 0.0839);
MVP		0.85
ClinPred		0.98	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.60

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: rs773942629; hg19: chr19-11547005;