rs121918360

Positions:

• chr5-77349456-A-C
• chr5-77349456-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The ENST00000264917.10(PDE8B):​c.914A>C​(p.His305Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE8B ENST00000264917.10 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.87

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 Likely_pathogenic. Variant got 6 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 5-77349456-A-C is Pathogenic according to our data. Variant chr5-77349456-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 6390.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE8B	NM_003719.5	c.914A>C	p.His305Pro	missense_variant	8/22	ENST00000264917.10	NP_003710.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE8B	ENST00000264917.10	c.914A>C	p.His305Pro	missense_variant	8/22	1	NM_003719.5	ENSP00000264917	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pigmented nodular adrenocortical disease, primary, 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 14, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.65	.;D;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.024
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.63	T;T;T;T;T
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	0.34	.;N;.;N;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.1	.;N;N;D;D
REVEL	Pathogenic	0.78
Sift	Benign	0.064	.;T;T;T;T
Sift4G	Benign	0.099	.;T;T;T;T
Polyphen		0.49, 0.44	.;P;B;B;.
Vest4		0.44, 0.45, 0.45
MutPred		0.81		.;Gain of ubiquitination at K306 (P = 0.0561);.;Gain of ubiquitination at K306 (P = 0.0561);.;
MVP		0.96
MPC		2.1
ClinPred		0.76	D
GERP RS		4.6
Varity_R		0.50
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121918360; hg19: chr5-76645281;