chr2-182168293-G-GA

Variant names:

• chr2-182168293-G-GA
• rs78156757
• NM_001363871.4:c.1516+17598dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001003683.3(PDE1A):​c.1565-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0825 in 1,126,766 control chromosomes in the GnomAD database, including 21 homozygotes. 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 0.010 (16 hom., cov: 25)
  • Exomes 𝑓: 0.092 (5 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0105 (1421/135798) while in subpopulation AFR AF = 0.0279 (1039/37194). AF 95% confidence interval is 0.0265. There are 16 homozygotes in GnomAd4. There are 675 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 gene

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+17598dupT		intron	N/A	NP_001350800.1	P54750-6
	PDE1A	NM_001258312.3		c.1576+17598dupT		intron	N/A	NP_001245241.1
	PDE1A	NM_001395258.2		c.1564+17598dupT		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+17598_1516+17599insT		intron	N/A	ENSP00000386767.1	P54750-6
	PDE1A	ENST00000435564.6	TSL:1	c.1564+17598_1564+17599insT		intron	N/A	ENSP00000410309.1	P54750-4
	PDE1A	ENST00000410103.2	TSL:1	c.1565-4_1565-3insT		splice_region intron	N/A	ENSP00000387037.1	P54750-1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1410 AN: 135738 Hom.: 16 Cov.: 25

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00594

Gnomad ASJ AF: 0.0237

Gnomad EAS AF: 0.000825

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.00313

Gnomad MID AF: 0.00352

Gnomad NFE AF: 0.00145

Gnomad OTH AF: 0.0109

GnomAD2 exomes AF: 0.0932 AC: 10718 AN: 114962 AF XY: 0.0976

Gnomad AFR exome AF: 0.0911

Gnomad AMR exome AF: 0.0575

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.0655

Gnomad FIN exome AF: 0.100

Gnomad NFE exome AF: 0.0913

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0924 AC: 91530 AN: 990968 Hom.: 5 Cov.: 0 AF XY: 0.0930 AC XY: 45666 AN XY: 490966

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

African (AFR) AF: 0.103 AC: 2296 AN: 22238

American (AMR) AF: 0.0553 AC: 1421 AN: 25694

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 2205 AN: 16110

East Asian (EAS) AF: 0.0534 AC: 1526 AN: 28586

South Asian (SAS) AF: 0.108 AC: 6243 AN: 57556

European-Finnish (FIN) AF: 0.0897 AC: 3070 AN: 34236

Middle Eastern (MID) AF: 0.0712 AC: 278 AN: 3906

European-Non Finnish (NFE) AF: 0.0927 AC: 70698 AN: 762392

Other (OTH) AF: 0.0942 AC: 3793 AN: 40250

⚠️ 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: 0.0105 AC: 1421 AN: 135798 Hom.: 16 Cov.: 25 AF XY: 0.0103 AC XY: 675 AN XY: 65354

African (AFR) AF: 0.0279 AC: 1039 AN: 37194

American (AMR) AF: 0.00593 AC: 82 AN: 13828

Ashkenazi Jewish (ASJ) AF: 0.0237 AC: 76 AN: 3208

East Asian (EAS) AF: 0.000828 AC: 4 AN: 4832

South Asian (SAS) AF: 0.0197 AC: 86 AN: 4372

European-Finnish (FIN) AF: 0.00313 AC: 23 AN: 7344

Middle Eastern (MID) AF: 0.00376 AC: 1 AN: 266

European-Non Finnish (NFE) AF: 0.00145 AC: 90 AN: 62062

Other (OTH) AF: 0.0108 AC: 20 AN: 1850

Alfa AF: 0.0537 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)		0.070		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: COSV59520427;