chr21-42731911-C-T

Variant names:

• chr21-42731911-C-T
• rs762900988
• NM_002606.3:c.404C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002606.3(PDE9A):​c.404C>T​(p.Pro135Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: PDE9A NM_002606.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0460
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02693522).

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.404C>T	p.Pro135Leu	missense	Exon 5 of 20	NP_002597.1	O76083-1
	PDE9A	NM_001001583.2		c.326C>T	p.Pro109Leu	missense	Exon 4 of 19	NP_001001583.1	O76083-15
	PDE9A	NM_001001582.2		c.281C>T	p.Pro94Leu	missense	Exon 4 of 19	NP_001001582.1	O76083-14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE9A	ENST00000291539.11	TSL:1 MANE Select	c.404C>T	p.Pro135Leu	missense	Exon 5 of 20	ENSP00000291539.6	O76083-1
	PDE9A	ENST00000328862.10	TSL:1	c.326C>T	p.Pro109Leu	missense	Exon 4 of 19	ENSP00000328699.6	O76083-15
	PDE9A	ENST00000398225.7	TSL:1	c.281C>T	p.Pro94Leu	missense	Exon 4 of 19	ENSP00000381281.3	O76083-14

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 250910 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: 0.000435

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461760 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727172

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

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

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111924

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

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	Benign	0.081
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.55
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.046
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.15
Sift	Uncertain	0.010	D
Sift4G	Benign	0.087	T
Polyphen		0.0020	B
Vest4		0.18
MutPred		0.22		Loss of loop (P = 0.0073)
MVP		0.47
MPC		0.28
ClinPred		0.052	T
GERP RS		1.9
Varity_R		0.097
gMVP		0.27
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs762900988; hg19: chr21-44152021; COSMIC: COSV52332604; COSMIC: COSV52332604;