chr15-84982325-C-G

Variant names:

• chr15-84982325-C-G
• rs11540803
• NM_002605.3:c.163C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002605.3(PDE8A):​c.163C>G​(p.Leu55Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0909 in 1,327,742 control chromosomes in the GnomAD database, including 6,037 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.066 (477 hom., cov: 32)
  • Exomes 𝑓: 0.094 (5560 hom.)
• Consequence: PDE8A NM_002605.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.109
• Publications: 8 publications found

Genes affected

PDE8A (HGNC:8793): (phosphodiesterase 8A) The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase (PDE) family, and PDE8 subfamily. This PDE hydrolyzes the second messenger, cAMP, which is a regulator and mediator of a number of cellular responses to extracellular signals. Thus, by regulating the cellular concentration of cAMP, this protein plays a key role in many important physiological processes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2011]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014356971).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0982 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE8A	NM_002605.3	c.163C>G	p.Leu55Val	missense_variant	Exon 1 of 22	ENST00000394553.6	NP_002596.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE8A	ENST00000394553.6	c.163C>G	p.Leu55Val	missense_variant	Exon 1 of 22	1	NM_002605.3	ENSP00000378056.1

Frequencies

GnomAD3 genomes AF: 0.0658 AC: 9993 AN: 151974 Hom.: 478 Cov.: 32

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0554

Gnomad ASJ AF: 0.0875

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.0687

Gnomad FIN AF: 0.0580

Gnomad MID AF: 0.0929

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.0766

GnomAD2 exomes AF: 0.0809 AC: 1137 AN: 14054 AF XY: 0.0877

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.0358

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0741

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.0648

GnomAD4 exome AF: 0.0942 AC: 110698 AN: 1175652 Hom.: 5560 Cov.: 31 AF XY: 0.0940 AC XY: 53365 AN XY: 567984

African (AFR) AF: 0.0153 AC: 365 AN: 23854

American (AMR) AF: 0.0510 AC: 502 AN: 9836

Ashkenazi Jewish (ASJ) AF: 0.0902 AC: 1437 AN: 15934

East Asian (EAS) AF: 0.000289 AC: 8 AN: 27710

South Asian (SAS) AF: 0.0729 AC: 3282 AN: 45042

European-Finnish (FIN) AF: 0.0541 AC: 1479 AN: 27330

Middle Eastern (MID) AF: 0.113 AC: 416 AN: 3684

European-Non Finnish (NFE) AF: 0.102 AC: 99165 AN: 974526

Other (OTH) AF: 0.0847 AC: 4044 AN: 47736

GnomAD4 genome AF: 0.0657 AC: 9985 AN: 152090 Hom.: 477 Cov.: 32 AF XY: 0.0630 AC XY: 4686 AN XY: 74356

African (AFR) AF: 0.0200 AC: 830 AN: 41542

American (AMR) AF: 0.0553 AC: 845 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0875 AC: 303 AN: 3464

East Asian (EAS) AF: 0.000969 AC: 5 AN: 5162

South Asian (SAS) AF: 0.0681 AC: 329 AN: 4832

European-Finnish (FIN) AF: 0.0580 AC: 614 AN: 10582

Middle Eastern (MID) AF: 0.0862 AC: 25 AN: 290

European-Non Finnish (NFE) AF: 0.100 AC: 6805 AN: 67910

Other (OTH) AF: 0.0754 AC: 159 AN: 2110

Alfa AF: 0.0794 Hom.: 79

Bravo AF: 0.0634

TwinsUK AF: 0.0944 AC: 350

ALSPAC AF: 0.0950 AC: 366

ESP6500AA AF: 0.0127 AC: 23

ESP6500EA AF: 0.0709 AC: 331

ExAC AF: 0.0442 AC: 4047

Asia WGS AF: 0.0200 AC: 70 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.7
DANN	Benign	0.50
DEOGEN2	Benign	0.064	T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.29	T;.;T
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N
PhyloP100		0.11
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.010	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.30	T;T;T
Sift4G	Benign	0.76	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.023
MPC		0.19
ClinPred		0.0031	T
GERP RS		-1.3
PromoterAI		-0.037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.040
gMVP		0.098
Mutation Taster		=99/1	polymorphism (auto)

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

dbSNP: rs11540803; hg19: chr15-85525556; COSMIC: COSV59636538;