NM_002606.3:c.83A>C

Variant names:

• chr21-42686205-A-C
• rs762935472
• NM_002606.3:c.83A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002606.3(PDE9A):​c.83A>C​(p.Lys28Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PDE9A NM_002606.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95
• Publications: 0 publications found

Genes affected

PDE9A (HGNC:8795): (phosphodiesterase 9A) The protein encoded by this gene catalyzes the hydrolysis of cAMP and cGMP to their corresponding monophosphates. The encoded protein plays a role in signal transduction by regulating the intracellular concentration of these cyclic nucleotides. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25039607).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002606.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE9A	NM_002606.3	MANE Select	c.83A>C	p.Lys28Thr	missense	Exon 2 of 20	NP_002597.1	O76083-1
	PDE9A	NM_001001583.2		c.83A>C	p.Lys28Thr	missense	Exon 2 of 19	NP_001001583.1	O76083-15
	PDE9A	NM_001001570.2		c.83A>C	p.Lys28Thr	missense	Exon 2 of 19	NP_001001570.1	O76083-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE9A	ENST00000291539.11	TSL:1 MANE Select	c.83A>C	p.Lys28Thr	missense	Exon 2 of 20	ENSP00000291539.6	O76083-1
	PDE9A	ENST00000328862.10	TSL:1	c.83A>C	p.Lys28Thr	missense	Exon 2 of 19	ENSP00000328699.6	O76083-15
	PDE9A	ENST00000380328.6	TSL:1	c.83A>C	p.Lys28Thr	missense	Exon 2 of 19	ENSP00000369685.2	O76083-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251392 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461522 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727098

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111728

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.092	T
Eigen	Benign	0.011
Eigen_PC	Benign	0.080
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.16
Sift	Benign	0.42	T
Sift4G	Benign	0.33	T
Polyphen		0.48	P
Vest4		0.68
MutPred		0.41		Loss of ubiquitination at K28 (P = 0.027)
MVP		0.77
MPC		0.65
ClinPred		0.51	D
GERP RS		3.8
Varity_R		0.085
gMVP		0.67
Mutation Taster		=68/32	polymorphism

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: rs762935472; hg19: chr21-44106315;