5-77210944-A-G

Variant names:

• chr5-77210944-A-G
• rs1176143656
• NM_003719.5:c.19A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003719.5(PDE8B):​c.19A>G​(p.Ile7Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I7F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PDE8B NM_003719.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.06
• 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 2 ACMG points.

• 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.19A>G	p.Ile7Val	missense	Exon 1 of 22	NP_003710.1	O95263-1
	PDE8B	NM_001349749.3		c.19A>G	p.Ile7Val	missense	Exon 1 of 23	NP_001336678.1
	PDE8B	NM_001349748.3		c.19A>G	p.Ile7Val	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.19A>G	p.Ile7Val	missense	Exon 1 of 22	ENSP00000264917.6	O95263-1
	PDE8B	ENST00000342343.8	TSL:1	c.19A>G	p.Ile7Val	missense	Exon 1 of 21	ENSP00000345646.4	O95263-4
	PDE8B	ENST00000340978.7	TSL:1	c.19A>G	p.Ile7Val	missense	Exon 1 of 21	ENSP00000345446.3	O95263-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1356038 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 673084

African (AFR) AF: 0.00 AC: 0 AN: 28290

American (AMR) AF: 0.00 AC: 0 AN: 33910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23254

East Asian (EAS) AF: 0.00 AC: 0 AN: 30734

South Asian (SAS) AF: 0.00 AC: 0 AN: 76066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4884

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1068404

Other (OTH) AF: 0.00 AC: 0 AN: 55696

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T
Eigen	Benign	0.016
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.81	L
PhyloP100		7.1
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.27	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.033	D
Polyphen		0.88	P
Vest4		0.39
MutPred		0.62		Gain of catalytic residue at I7 (P = 0.1725)
MVP		0.59
MPC		1.7
ClinPred		0.73	D
GERP RS		2.7
PromoterAI		0.16	Neutral
Varity_R		0.16
gMVP		0.29
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: rs1176143656; hg19: chr5-76506769;