chr5-77427052-C-A

Position:

• chr5-77427052-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003719.5(PDE8B):​c.*498C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 141,570 control chromosomes in the GnomAD database, including 4,662 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4662 hom., cov: 31)
  • Exomes 𝑓: 0.22 (146 hom.)
  • Failed GnomAD Quality Control
• Consequence: PDE8B NM_003719.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.942

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]

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE8B	NM_003719.5	c.*498C>A		3_prime_UTR_variant	22/22	ENST00000264917.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE8B	ENST00000264917.10	c.*498C>A		3_prime_UTR_variant	22/22	1	NM_003719.5	P1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 35162 AN: 141492 Hom.: 4662 Cov.: 31

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.224

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.242

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.220 AC: 1132 AN: 5140 Hom.: 146 Cov.: 0 AF XY: 0.211 AC XY: 558 AN XY: 2640

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.185

Gnomad4 ASJ exome AF: 0.357

Gnomad4 EAS exome AF: 0.0805

Gnomad4 SAS exome AF: 0.146

Gnomad4 FIN exome AF: 0.171

Gnomad4 NFE exome AF: 0.254

Gnomad4 OTH exome AF: 0.223

GnomAD4 genome AF: 0.248 AC: 35173 AN: 141570 Hom.: 4662 Cov.: 31 AF XY: 0.247 AC XY: 17093 AN XY: 69150

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.444

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.156

Gnomad4 FIN AF: 0.340

Gnomad4 NFE AF: 0.315

Gnomad4 OTH AF: 0.240

Alfa AF: 0.139 Hom.: 453

Bravo AF: 0.224

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant striatal neurodegeneration type 1 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.61
DANN	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs1061405; hg19: chr5-76722877;