chr7-31775712-C-T

Variant names:

• chr7-31775712-C-T
• rs74905175
• NM_001191057.4:c.1912G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001191057.4(PDE1C):​c.1912G>A​(p.Gly638Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,612,688 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (50 hom.)
• Consequence: PDE1C NM_001191057.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.390
• Publications: 2 publications found

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]

PDE1C Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal dominant 74

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002098769).
• BP6: Variant 7-31775712-C-T is Benign according to our data. Variant chr7-31775712-C-T is described in ClinVar as Benign. ClinVar VariationId is 3038497.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0526 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001191057.4. 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
	PDE1C	NM_001191057.4	MANE Select	c.1912G>A	p.Gly638Ser	missense	Exon 17 of 18	NP_001177986.1	Q14123-1
	PDE1C	NM_001191058.4		c.2092G>A	p.Gly698Ser	missense	Exon 18 of 19	NP_001177987.2	A0A0A0MS69
	PDE1C	NM_001191059.4		c.1912G>A	p.Gly638Ser	missense	Exon 18 of 19	NP_001177988.1	Q14123-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE1C	ENST00000396191.6	TSL:2 MANE Select	c.1912G>A	p.Gly638Ser	missense	Exon 17 of 18	ENSP00000379494.1	Q14123-1
	PDE1C	ENST00000396193.5	TSL:2	c.2092G>A	p.Gly698Ser	missense	Exon 18 of 19	ENSP00000379496.1	A0A0A0MS69
	PDE1C	ENST00000321453.12	TSL:2	c.1912G>A	p.Gly638Ser	missense	Exon 18 of 19	ENSP00000318105.7	Q14123-1

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 360 AN: 152030 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000677

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0585

Gnomad SAS AF: 0.00229

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00519 AC: 1253 AN: 241536 AF XY: 0.00475

Gnomad AFR exome AF: 0.000490

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.0659

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000103

Gnomad OTH exome AF: 0.00201

GnomAD4 exome AF: 0.00168 AC: 2447 AN: 1460540 Hom.: 50 Cov.: 30 AF XY: 0.00163 AC XY: 1185 AN XY: 726564

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26136

East Asian (EAS) AF: 0.0512 AC: 2034 AN: 39696

South Asian (SAS) AF: 0.00131 AC: 113 AN: 86248

European-Finnish (FIN) AF: 0.0000956 AC: 5 AN: 52308

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000103 AC: 114 AN: 1111826

Other (OTH) AF: 0.00250 AC: 151 AN: 60362

GnomAD4 genome AF: 0.00235 AC: 357 AN: 152148 Hom.: 8 Cov.: 32 AF XY: 0.00265 AC XY: 197 AN XY: 74378

African (AFR) AF: 0.000675 AC: 28 AN: 41508

American (AMR) AF: 0.000458 AC: 7 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0580 AC: 300 AN: 5168

South Asian (SAS) AF: 0.00229 AC: 11 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68006

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000432 Hom.: 1

Bravo AF: 0.00292

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00515 AC: 604

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PDE1C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.3
DANN	Benign	0.57
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.39
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.15
Sift	Benign	0.26	T
Sift4G	Benign	0.52	T
Polyphen		0.25	B
Vest4		0.28
MVP		0.38
MPC		0.029
ClinPred		0.0062	T
GERP RS		2.6
Varity_R		0.033
gMVP		0.24
Mutation Taster		=97/3	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs74905175; hg19: chr7-31815326; COSMIC: COSV58515013;