2-182168293-GAAA-GA

Variant names:

• chr2-182168293-GAA-G
• rs78156757
• NM_001363871.4:c.1516+17597_1516+17598delTT

Variant summary

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

The NM_001003683.3(PDE1A):​c.1565-5_1565-4delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,308,412 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 25)
  • Exomes 𝑓: 0.00070 (0 hom.)
• Consequence: PDE1A NM_001003683.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.659
• 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 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001003683.3. 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
	PDE1A	NM_001363871.4	MANE Select	c.1516+17597_1516+17598delTT		intron	N/A	NP_001350800.1	P54750-6
	PDE1A	NM_001258312.3		c.1576+17597_1576+17598delTT		intron	N/A	NP_001245241.1
	PDE1A	NM_001395258.2		c.1564+17597_1564+17598delTT		intron	N/A	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.1516+17597_1516+17598delTT		intron	N/A	ENSP00000386767.1	P54750-6
	PDE1A	ENST00000435564.6	TSL:1	c.1564+17597_1564+17598delTT		intron	N/A	ENSP00000410309.1	P54750-4
	PDE1A	ENST00000410103.2	TSL:1	c.1565-5_1565-4delTT		splice_region intron	N/A	ENSP00000387037.1	P54750-1

Frequencies

GnomAD3 genomes AF: 0.000228 AC: 31 AN: 135880 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000296

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000145

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00227

Gnomad SAS AF: 0.000682

Gnomad FIN AF: 0.000136

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000483

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00266 AC: 306 AN: 114962 AF XY: 0.00236

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.00591

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00623

Gnomad FIN exome AF: 0.00119

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.00241

GnomAD4 exome AF: 0.000696 AC: 816 AN: 1172472 Hom.: 0 AF XY: 0.000683 AC XY: 398 AN XY: 582966

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

African (AFR) AF: 0.00140 AC: 36 AN: 25732

American (AMR) AF: 0.00356 AC: 99 AN: 27844

Ashkenazi Jewish (ASJ) AF: 0.000593 AC: 12 AN: 20236

East Asian (EAS) AF: 0.00184 AC: 60 AN: 32694

South Asian (SAS) AF: 0.00183 AC: 117 AN: 63902

European-Finnish (FIN) AF: 0.000622 AC: 26 AN: 41796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4580

European-Non Finnish (NFE) AF: 0.000466 AC: 423 AN: 907526

Other (OTH) AF: 0.000893 AC: 43 AN: 48162

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000221 AC: 30 AN: 135940 Hom.: 0 Cov.: 25 AF XY: 0.000183 AC XY: 12 AN XY: 65448

African (AFR) AF: 0.000296 AC: 11 AN: 37210

American (AMR) AF: 0.000145 AC: 2 AN: 13840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3210

East Asian (EAS) AF: 0.00207 AC: 10 AN: 4836

South Asian (SAS) AF: 0.000686 AC: 3 AN: 4374

European-Finnish (FIN) AF: 0.000136 AC: 1 AN: 7374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.0000483 AC: 3 AN: 62136

Other (OTH) AF: 0.00 AC: 0 AN: 1852

Alfa AF: 0.00230 Hom.: 98

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.66
Mutation Taster		=100/0	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: rs78156757; hg19: chr2-183033020; COSMIC: COSV59518888;