2-182168293-GAAA-GAAAAAAAA

Variant names:

• chr2-182168293-G-GAAAAA
• rs78156757
• NM_001363871.4:c.1516+17594_1516+17598dupTTTTT

Variant summary

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

The NM_001003683.3(PDE1A):​c.1565-8_1565-4dupTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000849 in 1,178,410 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: not found (cov: 25)
  • Exomes 𝑓: 8.5e-7 (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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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+17594_1516+17598dupTTTTT		intron	N/A	NP_001350800.1	P54750-6
	PDE1A	NM_001258312.3		c.1576+17594_1576+17598dupTTTTT		intron	N/A	NP_001245241.1
	PDE1A	NM_001395258.2		c.1564+17594_1564+17598dupTTTTT		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+17599insTTTTT		intron	N/A	ENSP00000386767.1	P54750-6
	PDE1A	ENST00000435564.6	TSL:1	c.1564+17598_1564+17599insTTTTT		intron	N/A	ENSP00000410309.1	P54750-4
	PDE1A	ENST00000410103.2	TSL:1	c.1565-4_1565-3insTTTTT		splice_region intron	N/A	ENSP00000387037.1	P54750-1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 8.49e-7 AC: 1 AN: 1178410 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 586114

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

African (AFR) AF: 0.00 AC: 0 AN: 25852

American (AMR) AF: 0.00 AC: 0 AN: 28138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20328

East Asian (EAS) AF: 0.0000303 AC: 1 AN: 32990

South Asian (SAS) AF: 0.00 AC: 0 AN: 64422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4596

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 911518

Other (OTH) AF: 0.00 AC: 0 AN: 48414

⚠️ 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 Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.66

Splicing

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

Other links and lift over

dbSNP: rs78156757; hg19: chr2-183033020;