rs121918360

Variant names:

• chr5-77349456-A-C
• rs121918360
• NM_003719.5:c.914A>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_003719.5(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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H305R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE8B NM_003719.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.87
• Publications: 23 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
PDE8B	NM_003719.5	c.914A>C	p.His305Pro	missense_variant	Exon 8 of 22	ENST00000264917.10	NP_003710.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE8B	ENST00000264917.10	c.914A>C	p.His305Pro	missense_variant	Exon 8 of 22	1	NM_003719.5	ENSP00000264917.6
PDE8B	ENST00000646262.1	c.542A>C	p.His181Pro	missense_variant	Exon 10 of 24			ENSP00000493971.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pigmented nodular adrenocortical disease, primary, 3 Pathogenic:1

Feb 14, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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;.
PhyloP100		3.9
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918360; hg19: chr5-76645281;