5-77426544-C-CT

Variant names:

• chr5-77426544-C-CT
• rs1798184496
• NM_003719.5:c.2649dupT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_003719.5(PDE8B):​c.2649dupT​(p.Asp884fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE8B NM_003719.5 frameshift, stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0630
• Publications: 0 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 (HGNC:):

WDR41 (HGNC:25601): (WD repeat domain 41) Contributes to guanyl-nucleotide exchange factor activity. Involved in regulation of autophagy. Located in cytoplasm. Part of guanyl-nucleotide exchange factor complex. Colocalizes with Atg1/ULK1 kinase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00301 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.2649dupT	p.Asp884fs	frameshift stop_gained	Exon 22 of 22	NP_003710.1	O95263-1
	PDE8B	NM_001349749.3		c.2712dupT	p.Asp905fs	frameshift stop_gained	Exon 23 of 23	NP_001336678.1
	PDE8B	NM_001349748.3		c.2646dupT	p.Asp883fs	frameshift stop_gained	Exon 22 of 22	NP_001336677.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE8B	ENST00000264917.10	TSL:1 MANE Select	c.2649dupT	p.Asp884fs	frameshift stop_gained	Exon 22 of 22	ENSP00000264917.6	O95263-1
	PDE8B	ENST00000342343.8	TSL:1	c.2589dupT	p.Asp864fs	frameshift stop_gained	Exon 21 of 21	ENSP00000345646.4	O95263-4
	PDE8B	ENST00000340978.7	TSL:1	c.2508dupT	p.Asp837fs	frameshift stop_gained	Exon 21 of 21	ENSP00000345446.3	O95263-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant striatal neurodegeneration type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.063

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1798184496; hg19: chr5-76722369;