rs79008179

Variant names:

• chr5-77408888-G-A
• rs79008179
• NM_003719.5:c.1366-5G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003719.5(PDE8B):​c.1366-5G>A variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.00005541
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.416
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant striatal neurodegeneration type 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pigmented nodular adrenocortical disease, primary, 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• primary pigmented nodular adrenocortical disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• striatal degeneration, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

PDE8B (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 354162.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 = 0.0242 (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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3687 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE8B	NM_003719.5	c.1366-5G>A		splice_region_variant, intron_variant	Intron 13 of 21	ENST00000264917.10	NP_003710.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE8B	ENST00000264917.10	c.1366-5G>A		splice_region_variant, intron_variant	Intron 13 of 21	1	NM_003719.5	ENSP00000264917.6
PDE8B	ENST00000646262.1	c.994-5G>A		splice_region_variant, intron_variant	Intron 15 of 23			ENSP00000493971.1

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3689 AN: 152150 Hom.: 49 Cov.: 32

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

GnomAD2 exomes AF: 0.0224 AC: 5622 AN: 251310 AF XY: 0.0224

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 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.: 30 AF XY: 0.0281 AC XY: 20396 AN XY: 725272

African (AFR) AF: 0.0191 AC: 639 AN: 33390

American (AMR) AF: 0.00747 AC: 334 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0201 AC: 526 AN: 26112

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39676

South Asian (SAS) AF: 0.00530 AC: 457 AN: 86162

European-Finnish (FIN) AF: 0.0327 AC: 1745 AN: 53398

Middle Eastern (MID) AF: 0.0213 AC: 123 AN: 5764

European-Non Finnish (NFE) AF: 0.0330 AC: 36564 AN: 1107666

Other (OTH) AF: 0.0243 AC: 1463 AN: 60234

GnomAD4 genome AF: 0.0242 AC: 3687 AN: 152268 Hom.: 49 Cov.: 32 AF XY: 0.0236 AC XY: 1757 AN XY: 74448

African (AFR) AF: 0.0191 AC: 793 AN: 41552

American (AMR) AF: 0.0105 AC: 161 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4818

European-Finnish (FIN) AF: 0.0286 AC: 303 AN: 10598

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0334 AC: 2272 AN: 68034

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.0280 Hom.: 63

Bravo AF: 0.0235

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 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. -

PDE8B-related disorder Benign:1

Sep 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs79008179; hg19: chr5-76704713;