19-11435654-C-T

Variant names:

• chr19-11435654-C-T
• rs45450094
• NM_001289104.2:c.-130C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001289104.2(PRKCSH):​c.-130C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00936 in 1,286,194 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0096 (65 hom.)
• Consequence: PRKCSH NM_001289104.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.145

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]

ODAD3 (HGNC:28303): (outer dynein arm docking complex subunit 3) This gene encodes a protein containing coiled-coil domains. The encoded protein functions in outer dynein arm assembly and is required for motile cilia function. Mutations in this gene result in primary ciliary dyskinesia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 19-11435654-C-T is Benign according to our data. Variant chr19-11435654-C-T is described in ClinVar as [Benign]. Clinvar id is 328166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00736 (1121/152296) while in subpopulation NFE AF= 0.0107 (729/68026). AF 95% confidence interval is 0.0101. There are 11 homozygotes in gnomad4. There are 537 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1121 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCSH	NM_001289104.2	c.-130C>T		5_prime_UTR_variant	Exon 1 of 18	ENST00000677123.1	NP_001276033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCSH	ENST00000677123	c.-130C>T		5_prime_UTR_variant	Exon 1 of 18		NM_001289104.2	ENSP00000503163.1

Frequencies

GnomAD3 genomes AF: 0.00736 AC: 1120 AN: 152176 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.00786

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00792

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00643 AC: 838 AN: 130294 Hom.: 8 AF XY: 0.00608 AC XY: 432 AN XY: 71078

Gnomad AFR exome AF: 0.00230

Gnomad AMR exome AF: 0.00505

Gnomad ASJ exome AF: 0.00593

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00156

Gnomad FIN exome AF: 0.00762

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.00963 AC: 10922 AN: 1133898 Hom.: 65 Cov.: 25 AF XY: 0.00933 AC XY: 5196 AN XY: 557024

Gnomad4 AFR exome AF: 0.00163

Gnomad4 AMR exome AF: 0.00531

Gnomad4 ASJ exome AF: 0.00565

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00183

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.0109

Gnomad4 OTH exome AF: 0.00810

GnomAD4 genome AF: 0.00736 AC: 1121 AN: 152296 Hom.: 11 Cov.: 33 AF XY: 0.00721 AC XY: 537 AN XY: 74470

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00785

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00792

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00589 Hom.: 1

Bravo AF: 0.00774

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic liver disease 1 Benign:1

Jan 12, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.5
DANN	Benign	0.92

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs45450094; hg19: chr19-11546475; COSMIC: COSV105868888; COSMIC: COSV105868888;