rs202096938

Variant names:

• chr2-182186483-G-A
• rs202096938
• NM_001363871.4:c.1313C>T

Variant summary

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

The NM_001363871.4(PDE1A):​c.1313C>T​(p.Ser438Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,612,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: PDE1A NM_001363871.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26
• Publications: 1 publications found

Genes affected

PDE1A (HGNC:8774): (phosphodiesterase 1A) Cyclic nucleotide phosphodiesterases (PDEs) play a role in signal transduction by regulating intracellular cyclic nucleotide concentrations through hydrolysis of cAMP and/or cGMP to their respective nucleoside 5-prime monophosphates. Members of the PDE1 family, such as PDE1A, are Ca(2+)/calmodulin (see CALM1; MIM 114180)-dependent PDEs (CaM-PDEs) that are activated by calmodulin in the presence of Ca(2+) (Michibata et al., 2001 [PubMed 11342109]; Fidock et al., 2002 [PubMed 11747989]).[supplied by OMIM, Oct 2009]

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=0.39656278).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363871.4. 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
	PDE1A	NM_001363871.4	MANE Select	c.1313C>T	p.Ser438Phe	missense	Exon 12 of 15	NP_001350800.1	P54750-6
	PDE1A	NM_001258312.3		c.1373C>T	p.Ser458Phe	missense	Exon 13 of 16	NP_001245241.1
	PDE1A	NM_001395258.2		c.1361C>T	p.Ser454Phe	missense	Exon 13 of 16	NP_001382187.1	P54750-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE1A	ENST00000409365.6	TSL:5 MANE Select	c.1313C>T	p.Ser438Phe	missense	Exon 12 of 15	ENSP00000386767.1	P54750-6
	PDE1A	ENST00000435564.6	TSL:1	c.1361C>T	p.Ser454Phe	missense	Exon 12 of 15	ENSP00000410309.1	P54750-4
	PDE1A	ENST00000410103.2	TSL:1	c.1361C>T	p.Ser454Phe	missense	Exon 13 of 15	ENSP00000387037.1	P54750-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249574 AF XY: 0.00

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460298 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726360

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 44398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 85678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111628

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.00000756

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	0.13
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.17
Sift	Benign	0.071	T
Sift4G	Uncertain	0.044	D
Polyphen		0.13	B
Vest4		0.26
MutPred		0.34		Loss of disorder (P = 0.0103)
MVP		0.26
MPC		0.30
ClinPred		0.19	T
GERP RS		3.1
Varity_R		0.063
gMVP		0.29
Mutation Taster		=85/15	polymorphism

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: rs202096938; hg19: chr2-183051210; COSMIC: COSV59536038;