5-77210988-C-G

Position:

• chr5-77210988-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_003719.5(PDE8B):​c.63C>G​(p.Asp21Glu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. D21D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE8B NM_003719.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.365

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PDE8B. . Gene score misZ 2.9973 (greater than the threshold 3.09). Trascript score misZ 3.3776 (greater than threshold 3.09). GenCC has associacion of gene with pigmented nodular adrenocortical disease, primary, 3, autosomal dominant striatal neurodegeneration type 1, primary pigmented nodular adrenocortical disease, schizophrenia, striatal degeneration, autosomal dominant.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28272462).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE8B	NM_003719.5	c.63C>G	p.Asp21Glu	missense_variant	1/22	ENST00000264917.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE8B	ENST00000264917.10	c.63C>G	p.Asp21Glu	missense_variant	1/22	1	NM_003719.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2024

The c.63C>G (p.D21E) alteration is located in exon 1 (coding exon 1) of the PDE8B gene. This alteration results from a C to G substitution at nucleotide position 63, causing the aspartic acid (D) at amino acid position 21 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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	0.84
DEOGEN2	Benign	0.051	.;.;T;.;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.67	T;T;T;T;T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.28	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L;L;L;L
MutationTaster	Benign	0.50	N;N;N;N;N
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.64	N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.37	T;T;T;T;T
Sift4G	Benign	0.57	T;T;T;T;T
Polyphen		0.052	B;B;B;B;B
Vest4		0.10
MutPred		0.59		Gain of glycosylation at S23 (P = 0.1026);Gain of glycosylation at S23 (P = 0.1026);Gain of glycosylation at S23 (P = 0.1026);Gain of glycosylation at S23 (P = 0.1026);Gain of glycosylation at S23 (P = 0.1026);
MVP		0.54
MPC		0.79
ClinPred		0.21	T
GERP RS		-1.5
Varity_R		0.070
gMVP		0.40

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: rs201411330; hg19: chr5-76506813;