15-85113889-A-G

Variant names:

• chr15-85113889-A-G
• rs62019510
• NM_002605.3:c.1202A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000394553.6(PDE8A):​c.1202A>G​(p.Asn401Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0298 in 1,611,760 control chromosomes in the GnomAD database, including 869 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.022 (58 hom., cov: 32)
  • Exomes 𝑓: 0.031 (811 hom.)
• Consequence: PDE8A ENST00000394553.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04
• Publications: 18 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=0.0050416887).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0216 (3294/152326) while in subpopulation NFE AF = 0.0353 (2402/68028). AF 95% confidence interval is 0.0341. There are 58 homozygotes in GnomAd4. There are 1508 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 58 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000394553.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE8A	NM_002605.3	MANE Select	c.1202A>G	p.Asn401Ser	missense	Exon 14 of 22	NP_002596.1
	PDE8A	NM_173454.1		c.1064A>G	p.Asn355Ser	missense	Exon 13 of 21	NP_775656.1
	PDE8A	NM_001243137.2		c.986A>G	p.Asn329Ser	missense	Exon 14 of 22	NP_001230066.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE8A	ENST00000394553.6	TSL:1 MANE Select	c.1202A>G	p.Asn401Ser	missense	Exon 14 of 22	ENSP00000378056.1
	PDE8A	ENST00000310298.8	TSL:1	c.1202A>G	p.Asn401Ser	missense	Exon 15 of 23	ENSP00000311453.4
	PDE8A	ENST00000339708.9	TSL:1	c.1064A>G	p.Asn355Ser	missense	Exon 13 of 21	ENSP00000340679.5

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3293 AN: 152208 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.00545

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0397

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.0171

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0353

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0243 AC: 6067 AN: 249982 AF XY: 0.0246

Gnomad AFR exome AF: 0.00560

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.0439

Gnomad EAS exome AF: 0.00114

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.0364

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0306 AC: 44683 AN: 1459434 Hom.: 811 Cov.: 30 AF XY: 0.0305 AC XY: 22120 AN XY: 726132

African (AFR) AF: 0.00539 AC: 180 AN: 33398

American (AMR) AF: 0.0106 AC: 470 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 1050 AN: 26078

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39684

South Asian (SAS) AF: 0.0163 AC: 1399 AN: 85978

European-Finnish (FIN) AF: 0.0210 AC: 1122 AN: 53406

Middle Eastern (MID) AF: 0.0267 AC: 154 AN: 5760

European-Non Finnish (NFE) AF: 0.0347 AC: 38553 AN: 1110326

Other (OTH) AF: 0.0288 AC: 1739 AN: 60300

GnomAD4 genome AF: 0.0216 AC: 3294 AN: 152326 Hom.: 58 Cov.: 32 AF XY: 0.0202 AC XY: 1508 AN XY: 74474

African (AFR) AF: 0.00548 AC: 228 AN: 41572

American (AMR) AF: 0.0138 AC: 211 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 138 AN: 3472

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.0131 AC: 63 AN: 4820

European-Finnish (FIN) AF: 0.0171 AC: 182 AN: 10624

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.0353 AC: 2402 AN: 68028

Other (OTH) AF: 0.0255 AC: 54 AN: 2114

Alfa AF: 0.0317 Hom.: 282

Bravo AF: 0.0208

TwinsUK AF: 0.0329 AC: 122

ALSPAC AF: 0.0319 AC: 123

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0378 AC: 325

ExAC AF: 0.0238 AC: 2894

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.0340

EpiControl AF: 0.0365

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.0
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.15
Sift	Benign	0.20	T
Sift4G	Benign	0.23	T
Polyphen		0.11	B
Vest4		0.12
MPC		0.16
ClinPred		0.039	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.094
gMVP		0.34
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs62019510; hg19: chr15-85657120; COSMIC: COSV99045637; COSMIC: COSV99045637;