chr5-77211020-T-C

Position:

• chr5-77211020-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM2 PM5 PP2 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. 14/21 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. V32?) has been classified as Pathogenic.

• 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

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-77211019-GT-C is described in ClinVar as [Pathogenic]. Clinvar id is 6391.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.
• PP5: Variant 5-77211020-T-C is Pathogenic according to our data. Variant chr5-77211020-T-C is described in ClinVar as [Pathogenic]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE8B	NM_003719.5	c.95T>C	p.Val32Ala	missense_variant	1/22	ENST00000264917.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE8B	ENST00000264917.10	c.95T>C	p.Val32Ala	missense_variant	1/22	1	NM_003719.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Jun 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	0.0	N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.24	T;T;T;T;T
Sift4G	Benign	0.54	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.086
MutPred		0.47		Gain of relative solvent accessibility (P = 0.0249);Gain of relative solvent accessibility (P = 0.0249);Gain of relative solvent accessibility (P = 0.0249);Gain of relative solvent accessibility (P = 0.0249);Gain of relative solvent accessibility (P = 0.0249);
MVP		0.16
MPC		0.94
ClinPred		0.13	T
GERP RS		0.19
Varity_R		0.082
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-76506845;