2-182201650-CAAAAA-CAAAAAAAAAAAA

Variant names:

• chr2-182201650-C-CAAAAAAA
• rs56413404
• NM_001363871.4:c.1004+31_1004+37dupTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001363871.4(PDE1A):​c.1004+31_1004+37dupTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0305 in 1,113,626 control chromosomes in the GnomAD database, including 294 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.035 (150 hom., cov: 0)
  • Exomes 𝑓: 0.031 (294 hom.)
  • Failed GnomAD Quality Control
• Consequence: PDE1A NM_001363871.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.543
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 294 gene

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.1004+31_1004+37dupTTTTTTT		intron	N/A	NP_001350800.1	P54750-6
	PDE1A	NM_001258312.3		c.1064+31_1064+37dupTTTTTTT		intron	N/A	NP_001245241.1
	PDE1A	NM_001395258.2		c.1052+31_1052+37dupTTTTTTT		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.1004+37_1004+38insTTTTTTT		intron	N/A	ENSP00000386767.1	P54750-6
	PDE1A	ENST00000435564.6	TSL:1	c.1052+37_1052+38insTTTTTTT		intron	N/A	ENSP00000410309.1	P54750-4
	PDE1A	ENST00000410103.2	TSL:1	c.1052+37_1052+38insTTTTTTT		intron	N/A	ENSP00000387037.1	P54750-1

Frequencies

GnomAD3 genomes AF: 0.0353 AC: 4823 AN: 136484 Hom.: 148 Cov.: 0

Gnomad AFR AF: 0.00838

Gnomad AMI AF: 0.00113

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.0702

Gnomad EAS AF: 0.0695

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.0892

Gnomad MID AF: 0.0503

Gnomad NFE AF: 0.0363

Gnomad OTH AF: 0.0433

GnomAD4 exome AF: 0.0305 AC: 33997 AN: 1113626 Hom.: 294 Cov.: 25 AF XY: 0.0306 AC XY: 16972 AN XY: 555216

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

African (AFR) AF: 0.00597 AC: 148 AN: 24808

American (AMR) AF: 0.0481 AC: 973 AN: 20244

Ashkenazi Jewish (ASJ) AF: 0.0375 AC: 696 AN: 18584

East Asian (EAS) AF: 0.0624 AC: 2003 AN: 32090

South Asian (SAS) AF: 0.0211 AC: 1272 AN: 60396

European-Finnish (FIN) AF: 0.0588 AC: 2045 AN: 34794

Middle Eastern (MID) AF: 0.0230 AC: 105 AN: 4560

European-Non Finnish (NFE) AF: 0.0290 AC: 25226 AN: 870746

Other (OTH) AF: 0.0323 AC: 1529 AN: 47404

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0353 AC: 4823 AN: 136482 Hom.: 150 Cov.: 0 AF XY: 0.0370 AC XY: 2401 AN XY: 64954

African (AFR) AF: 0.00837 AC: 316 AN: 37752

American (AMR) AF: 0.0690 AC: 929 AN: 13456

Ashkenazi Jewish (ASJ) AF: 0.0702 AC: 236 AN: 3362

East Asian (EAS) AF: 0.0695 AC: 324 AN: 4660

South Asian (SAS) AF: 0.0205 AC: 87 AN: 4244

European-Finnish (FIN) AF: 0.0892 AC: 494 AN: 5540

Middle Eastern (MID) AF: 0.0620 AC: 17 AN: 274

European-Non Finnish (NFE) AF: 0.0363 AC: 2338 AN: 64430

Other (OTH) AF: 0.0431 AC: 81 AN: 1880

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.54
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56413404; hg19: chr2-183066377;