Genetic Variant PDE1A:c.1004+36_1004+37delTT (chr2-182201650-CAA-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001363871.4(PDE1A):c.1004+36_1004+37delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,268,222 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000029 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

PDE1A
NM_001363871.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.803

Publications

1 publications found

Variant links:

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]

PDE1A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PDE1A	NM_001363871.4	MANE Select	c.1004+36_1004+37delTT	intron	N/A	NP_001350800.1	P54750-6
PDE1A	NM_001258312.3		c.1064+36_1064+37delTT	intron	N/A	NP_001245241.1
PDE1A	NM_001395258.2		c.1052+36_1052+37delTT	intron	N/A	NP_001382187.1	P54750-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PDE1A	ENST00000409365.6	TSL:5 MANE Select	c.1004+36_1004+37delTT	intron	N/A	ENSP00000386767.1	P54750-6
PDE1A	ENST00000435564.6	TSL:1	c.1052+36_1052+37delTT	intron	N/A	ENSP00000410309.1	P54750-4
PDE1A	ENST00000410103.2	TSL:1	c.1052+36_1052+37delTT	intron	N/A	ENSP00000387037.1	P54750-1

Frequencies

GnomAD3 genomes

AF:

0.0000293

AC:

AN:

136748

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000106

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000194

AC:

AN:

1131474

Hom.:

AF XY:

0.0000195

AC XY:

AN XY:

564302

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000120

AC:

AN:

24910

American (AMR)

AF:

0.0000481

AC:

AN:

20788

Ashkenazi Jewish (ASJ)

AF:

0.0000524

AC:

AN:

19086

East Asian (EAS)

AF:

0.00

AC:

AN:

33680

South Asian (SAS)

AF:

0.0000328

AC:

AN:

61066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36000

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4618

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

882950

Other (OTH)

AF:

0.0000413

AC:

AN:

48376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000123276), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.357

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000293

AC:

AN:

136748

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

65080

show subpopulations

African (AFR)

AF:

0.000106

AC:

AN:

37724

American (AMR)

AF:

0.00

AC:

AN:

13486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3372

East Asian (EAS)

AF:

0.00

AC:

AN:

4698

South Asian (SAS)

AF:

0.00

AC:

AN:

4274

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

298

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64544

Other (OTH)

AF:

0.00

AC:

AN:

1876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.80

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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2-182201650-CAAAAA-CAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over