19-11435448-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The ENST00000676823.1(PRKCSH):c.-140+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 359,886 control chromosomes in the GnomAD database, including 723 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.052 (305 hom., cov: 33)
  • Exomes 𝑓: 0.057 (418 hom.)
• Consequence: PRKCSH ENST00000676823.1 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.0008653
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.395

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 19-11435448-G-A is Benign according to our data. Variant chr19-11435448-G-A is described in ClinVar as [Benign]. Clinvar id is 328161.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ODAD3	NM_001302453.1	c.82+242C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKCSH	ENST00000591946.5	c.-336G>A		5_prime_UTR_variant	1/3	2
ODAD3	ENST00000586836.5	c.-330+242C>T		intron_variant		2		A2
PRKCSH	ENST00000676823.1	c.-140+5G>A		splice_donor_5th_base_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.0518 AC: 7879 AN: 152146 Hom.: 305 Cov.: 33

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.0862

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.0401

Gnomad FIN AF: 0.0473

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0581

Gnomad OTH AF: 0.0656

GnomAD4 exome AF: 0.0571 AC: 11853 AN: 207622 Hom.: 418 Cov.: 4 AF XY: 0.0567 AC XY: 6395 AN XY: 112706

Gnomad4 AFR exome AF: 0.0134

Gnomad4 AMR exome AF: 0.138

Gnomad4 ASJ exome AF: 0.0897

Gnomad4 EAS exome AF: 0.0293

Gnomad4 SAS exome AF: 0.0524

Gnomad4 FIN exome AF: 0.0518

Gnomad4 NFE exome AF: 0.0552

Gnomad4 OTH exome AF: 0.0576

GnomAD4 genome AF: 0.0518 AC: 7889 AN: 152264 Hom.: 305 Cov.: 33 AF XY: 0.0521 AC XY: 3881 AN XY: 74432

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.0862

Gnomad4 EAS AF: 0.0237

Gnomad4 SAS AF: 0.0408

Gnomad4 FIN AF: 0.0473

Gnomad4 NFE AF: 0.0582

Gnomad4 OTH AF: 0.0649

Alfa AF: 0.0556 Hom.: 411

Bravo AF: 0.0581

Asia WGS AF: 0.0450 AC: 158 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Polycystic liver disease 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	12
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00087
dbscSNV1_RF	Benign	0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs17426435; hg19: chr19-11546269;