rs79008179

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003719.5(PDE8B):c.1366-5G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,609,390 control chromosomes in the GnomAD database, including 772 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 49 hom., cov: 32)

Exomes 𝑓: 0.029 ( 723 hom. )

Consequence

PDE8B
NM_003719.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00005541

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.416

Variant links:

Genes affected

PDE8B (HGNC:8794): (phosphodiesterase 8B) The protein encoded by this gene is a cyclic nucleotide phosphodiesterase (PDE) that catalyzes the hydrolysis of the second messenger cAMP. The encoded protein, which does not hydrolyze cGMP, is resistant to several PDE inhibitors. Defects in this gene are a cause of autosomal dominant striatal degeneration (ADSD). Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2010]

PDE8B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 5-77408888-G-A is Benign according to our data. Variant chr5-77408888-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 354162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-77408888-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0242 (3687/152268) while in subpopulation NFE AF= 0.0334 (2272/68034). AF 95% confidence interval is 0.0323. There are 49 homozygotes in gnomad4. There are 1757 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 3689 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE8B	NM_003719.5 linkuse as main transcript	c.1366-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000264917.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE8B	ENST00000264917.10 linkuse as main transcript	c.1366-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003719.5	P1	O95263-1

Frequencies

GnomAD3 genomes

AF:

0.0242

AC:

3689

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0192

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0105

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.0286

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0334

Gnomad OTH

AF:

0.0138

GnomAD3 exomes

AF:

0.0224

AC:

5622

AN:

251310

Hom.:

AF XY:

0.0224

AC XY:

3041

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.0199

Gnomad AMR exome

AF:

0.00700

Gnomad ASJ exome

AF:

0.0199

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00519

Gnomad FIN exome

AF:

0.0309

Gnomad NFE exome

AF:

0.0342

Gnomad OTH exome

AF:

0.0235

GnomAD4 exome

AF:

0.0287

AC:

41854

AN:

1457122

Hom.:

723

Cov.:

AF XY:

0.0281

AC XY:

20396

AN XY:

725272

show subpopulations

Gnomad4 AFR exome

AF:

0.0191

Gnomad4 AMR exome

AF:

0.00747

Gnomad4 ASJ exome

AF:

0.0201

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00530

Gnomad4 FIN exome

AF:

0.0327

Gnomad4 NFE exome

AF:

0.0330

Gnomad4 OTH exome

AF:

0.0243

GnomAD4 genome

AF:

0.0242

AC:

3687

AN:

152268

Hom.:

Cov.:

AF XY:

0.0236

AC XY:

1757

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0191

Gnomad4 AMR

AF:

0.0105

Gnomad4 ASJ

AF:

0.0202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.0286

Gnomad4 NFE

AF:

0.0334

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0305

Hom.:

Bravo

AF:

0.0235

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC frequency. Insufficient evidence for gene-disease association. -

Autosomal dominant striatal neurodegeneration type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

PDE8B-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

Cadd

Benign

1.4

Dann

Benign

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000055

dbscSNV1_RF

Benign

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over