7-31815963-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001191057.4(PDE1C):c.1774T>G(p.Ser592Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0052 in 1,613,802 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (39 hom.)
• Consequence: PDE1C NM_001191057.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00600

Genes affected

PDE1C (HGNC:8776): (phosphodiesterase 1C) This gene encodes an enzyme that belongs to the 3'5'-cyclic nucleotide phosphodiesterase family. Members of this family catalyze hydrolysis of the cyclic nucleotides, cyclic adenosine monophosphate and cyclic guanosine monophosphate, to the corresponding nucleoside 5'-monophosphates. The enzyme encoded by this gene regulates proliferation and migration of vascular smooth muscle cells, and neointimal hyperplasia. This enzyme also plays a role in pathological vascular remodeling by regulating the stability of growth factor receptors, such as PDGF-receptor-beta. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004617542).
• BP6: Variant 7-31815963-A-C is Benign according to our data. Variant chr7-31815963-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2657379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 664 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE1C	NM_001191057.4	c.1774T>G	p.Ser592Ala	missense_variant	15/18	ENST00000396191.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE1C	ENST00000396191.6	c.1774T>G	p.Ser592Ala	missense_variant	15/18	2	NM_001191057.4	A1

Frequencies

GnomAD3 genomes AF: 0.00437 AC: 664 AN: 152008 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00528

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00687

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00415 AC: 1044 AN: 251368 Hom.: 4 AF XY: 0.00421 AC XY: 572 AN XY: 135860

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00605

Gnomad NFE exome AF: 0.00604

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00529 AC: 7734 AN: 1461676 Hom.: 39 Cov.: 32 AF XY: 0.00516 AC XY: 3755 AN XY: 727148

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.00389

Gnomad4 ASJ exome AF: 0.00459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00599

Gnomad4 NFE exome AF: 0.00607

Gnomad4 OTH exome AF: 0.00540

GnomAD4 genome AF: 0.00436 AC: 663 AN: 152126 Hom.: 2 Cov.: 33 AF XY: 0.00421 AC XY: 313 AN XY: 74356

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00528

Gnomad4 NFE AF: 0.00685

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00575 Hom.: 8

Bravo AF: 0.00416

ExAC AF: 0.00385 AC: 468

EpiCase AF: 0.00594

EpiControl AF: 0.00688

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

PDE1C: BP4, BS2 -

PDE1C-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	2.5
Dann	Benign	0.65
DEOGEN2	Benign	0.24	T;T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.54	T;.;T;.;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0046	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.27	N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.17	T;T;T;T;T
Sift4G	Benign	0.40	T;T;T;T;T
Polyphen		0.0	.;B;B;B;B
Vest4		0.10
MVP		0.35
MPC		0.026
ClinPred		0.0018	T
GERP RS		-3.4
Varity_R		0.050
gMVP		0.051

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

LitVar

Other links and lift over

dbSNP: rs2230175; hg19: chr7-31855577; COSMIC: COSV100373216;