5-77426618-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003719.5(PDE8B):c.*64G>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 0.572 in 830,778 control chromosomes in the GnomAD database, including 139,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.62 (30464 hom., cov: 32)
  • Exomes 𝑓: 0.56 (109207 hom.)
• Consequence: PDE8B NM_003719.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.564

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-77426618-G-A is Benign according to our data. Variant chr5-77426618-G-A is described in ClinVar as [Benign]. Clinvar id is 354179.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE8B	NM_003719.5	c.*64G>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.*64G>A		3_prime_UTR_variant	22/22	1	NM_003719.5	P1

Frequencies

GnomAD3 genomes AF: 0.618 AC: 93974 AN: 152010 Hom.: 30412 Cov.: 32

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.620

GnomAD4 exome AF: 0.561 AC: 380897 AN: 678650 Hom.: 109207 Cov.: 9 AF XY: 0.562 AC XY: 204217 AN XY: 363334

Gnomad4 AFR exome AF: 0.811

Gnomad4 AMR exome AF: 0.735

Gnomad4 ASJ exome AF: 0.712

Gnomad4 EAS exome AF: 0.604

Gnomad4 SAS exome AF: 0.645

Gnomad4 FIN exome AF: 0.494

Gnomad4 NFE exome AF: 0.514

Gnomad4 OTH exome AF: 0.582

GnomAD4 genome AF: 0.618 AC: 94084 AN: 152128 Hom.: 30464 Cov.: 32 AF XY: 0.618 AC XY: 45986 AN XY: 74394

Gnomad4 AFR AF: 0.809

Gnomad4 AMR AF: 0.669

Gnomad4 ASJ AF: 0.716

Gnomad4 EAS AF: 0.589

Gnomad4 SAS AF: 0.654

Gnomad4 FIN AF: 0.483

Gnomad4 NFE AF: 0.507

Gnomad4 OTH AF: 0.619

Alfa AF: 0.519 Hom.: 14527

Bravo AF: 0.646

Asia WGS AF: 0.625 AC: 2175 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Striatal Degeneration Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	5.5
Dann	Benign	0.81

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: rs40594; hg19: chr5-76722443; COSMIC: COSV53733647; COSMIC: COSV53733647;