chr21-42686229-T-C

Variant names:

• chr21-42686229-T-C
• rs767731909
• NM_002606.3:c.107T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002606.3(PDE9A):​c.107T>C​(p.Met36Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M36R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDE9A NM_002606.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.63
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41304865).

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.107T>C	p.Met36Thr	missense	Exon 2 of 20	NP_002597.1	O76083-1
	PDE9A	NM_001001583.2		c.107T>C	p.Met36Thr	missense	Exon 2 of 19	NP_001001583.1	O76083-15
	PDE9A	NM_001001570.2		c.107T>C	p.Met36Thr	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.107T>C	p.Met36Thr	missense	Exon 2 of 20	ENSP00000291539.6	O76083-1
	PDE9A	ENST00000328862.10	TSL:1	c.107T>C	p.Met36Thr	missense	Exon 2 of 19	ENSP00000328699.6	O76083-15
	PDE9A	ENST00000380328.6	TSL:1	c.107T>C	p.Met36Thr	missense	Exon 2 of 19	ENSP00000369685.2	O76083-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.083	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.28
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		0.48	P
Vest4		0.66
MutPred		0.40		Loss of stability (P = 0.0012)
MVP		0.76
MPC		0.42
ClinPred		0.75	D
GERP RS		4.9
Varity_R		0.14
gMVP		0.67
Mutation Taster		=27/173	disease causing

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: rs767731909; hg19: chr21-44106339;