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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003719.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE8B	NM_003719.5	MANE Select	c.1366-5G>A		splice_region intron	N/A	NP_003710.1
	PDE8B	NM_001349749.3		c.1429-5G>A		splice_region intron	N/A	NP_001336678.1
	PDE8B	NM_001349748.3		c.1363-5G>A		splice_region intron	N/A	NP_001336677.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE8B	ENST00000264917.10	TSL:1 MANE Select	c.1366-5G>A		splice_region intron	N/A	ENSP00000264917.6
	PDE8B	ENST00000342343.8	TSL:1	c.1306-5G>A		splice_region intron	N/A	ENSP00000345646.4
	PDE8B	ENST00000340978.7	TSL:1	c.1225-5G>A		splice_region intron	N/A	ENSP00000345446.3

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant striatal neurodegeneration type 1 (1)
-	-	1	not specified (1)
-	-	1	PDE8B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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;