5-77211020-T-C

Variant names:

• chr5-77211020-T-C
• NM_003719.5:c.95T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_003719.5(PDE8B):​c.95T>C​(p.Val32Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V32M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE8B NM_003719.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.63
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-77211020-T-C is Pathogenic according to our data. Variant chr5-77211020-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1184955.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.121973544). . Strength limited to SUPPORTING due to the PP5.

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.95T>C	p.Val32Ala	missense	Exon 1 of 22	NP_003710.1	O95263-1
	PDE8B	NM_001349749.3		c.95T>C	p.Val32Ala	missense	Exon 1 of 23	NP_001336678.1
	PDE8B	NM_001349748.3		c.95T>C	p.Val32Ala	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.95T>C	p.Val32Ala	missense	Exon 1 of 22	ENSP00000264917.6	O95263-1
	PDE8B	ENST00000342343.8	TSL:1	c.95T>C	p.Val32Ala	missense	Exon 1 of 21	ENSP00000345646.4	O95263-4
	PDE8B	ENST00000340978.7	TSL:1	c.95T>C	p.Val32Ala	missense	Exon 1 of 21	ENSP00000345446.3	O95263-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

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	0.079
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.83
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.6
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	0.0	N
REVEL	Benign	0.17
Sift	Benign	0.24	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.086
MutPred		0.47		Gain of relative solvent accessibility (P = 0.0249)
MVP		0.16
MPC		0.94
ClinPred		0.13	T
GERP RS		0.19
PromoterAI		-0.031	Neutral
Varity_R		0.082
gMVP		0.27
Mutation Taster		=91/9	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

hg19: chr5-76506845;