NM_003719.5:c.63C>A

Variant names:

• chr5-77210988-C-A
• rs201411330
• NM_003719.5:c.63C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003719.5(PDE8B):​c.63C>A​(p.Asp21Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,390,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D21D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: PDE8B NM_003719.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.365
• 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 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29010475).

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.63C>A	p.Asp21Glu	missense	Exon 1 of 22	NP_003710.1	O95263-1
	PDE8B	NM_001349749.3		c.63C>A	p.Asp21Glu	missense	Exon 1 of 23	NP_001336678.1
	PDE8B	NM_001349748.3		c.63C>A	p.Asp21Glu	missense	Exon 1 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.63C>A	p.Asp21Glu	missense	Exon 1 of 22	ENSP00000264917.6	O95263-1
	PDE8B	ENST00000342343.8	TSL:1	c.63C>A	p.Asp21Glu	missense	Exon 1 of 21	ENSP00000345646.4	O95263-4
	PDE8B	ENST00000340978.7	TSL:1	c.63C>A	p.Asp21Glu	missense	Exon 1 of 21	ENSP00000345446.3	O95263-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1390084 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 2 AN XY: 690654

African (AFR) AF: 0.00 AC: 0 AN: 28908

American (AMR) AF: 0.00 AC: 0 AN: 38458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24196

East Asian (EAS) AF: 0.00 AC: 0 AN: 33064

South Asian (SAS) AF: 0.00 AC: 0 AN: 80190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5430

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1086420

Other (OTH) AF: 0.00 AC: 0 AN: 57584

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.36
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.12
Sift	Benign	0.37	T
Sift4G	Benign	0.57	T
Polyphen		0.052	B
Vest4		0.10
MutPred		0.59		Gain of glycosylation at S23 (P = 0.1026)
MVP		0.55
MPC		0.79
ClinPred		0.23	T
GERP RS		-1.5
PromoterAI		-0.014	Neutral
Varity_R		0.070
gMVP		0.40
Mutation Taster		=85/15	polymorphism

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: rs201411330; hg19: chr5-76506813;