16-2090679-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001009944.3(PKD1):c.12133A>G(p.Ile4045Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,611,784 control chromosomes in the GnomAD database, including 37,119 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 0.29 ( 9035 hom., cov: 34)

Exomes 𝑓: 0.18 ( 28084 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.239

Publications

40 publications found

Variant links:

Genes affected

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

PKD1 Gene-Disease associations (from GenCC):

autosomal dominant polycystic kidney disease
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
polycystic kidney disease 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
autosomal recessive polycystic kidney disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Caroli disease
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

PKD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.577714E-5).

BP6

Variant 16-2090679-T-C is Benign according to our data. Variant chr16-2090679-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.12133A>G	p.Ile4045Val	missense_variant	Exon 44 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 link	c.12133A>G	p.Ile4045Val	missense_variant	Exon 44 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes

AF:

0.288

AC:

43759

AN:

152030

Hom.:

9006

Cov.:

show subpopulations

Gnomad AFR

AF:

0.579

Gnomad AMI

AF:

0.0976

Gnomad AMR

AF:

0.203

Gnomad ASJ

AF:

0.254

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0922

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.179

Gnomad OTH

AF:

0.261

GnomAD2 exomes

AF:

0.181

AC:

44565

AN:

245684

AF XY:

0.175

show subpopulations

Gnomad AFR exome

AF:

0.581

Gnomad AMR exome

AF:

0.122

Gnomad ASJ exome

AF:

0.255

Gnomad EAS exome

AF:

0.000275

Gnomad FIN exome

AF:

0.222

Gnomad NFE exome

AF:

0.183

Gnomad OTH exome

AF:

0.190

GnomAD4 exome

AF:

0.181

AC:

263811

AN:

1459636

Hom.:

28084

Cov.:

AF XY:

0.177

AC XY:

128525

AN XY:

726110

show subpopulations

African (AFR)

AF:

0.585

AC:

19562

AN:

33462

American (AMR)

AF:

0.131

AC:

5864

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.261

AC:

6804

AN:

26108

East Asian (EAS)

AF:

0.000302

AC:

AN:

39696

South Asian (SAS)

AF:

0.0950

AC:

8193

AN:

86240

European-Finnish (FIN)

AF:

0.221

AC:

11402

AN:

51540

Middle Eastern (MID)

AF:

0.236

AC:

1361

AN:

5766

European-Non Finnish (NFE)

AF:

0.179

AC:

198819

AN:

1111798

Other (OTH)

AF:

0.195

AC:

11794

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

15081

30162

45243

60324

75405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7070

14140

21210

28280

35350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.288

AC:

43838

AN:

152148

Hom.:

9035

Cov.:

AF XY:

0.285

AC XY:

21189

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.579

AC:

24044

AN:

41502

American (AMR)

AF:

0.203

AC:

3099

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.254

AC:

881

AN:

3472

East Asian (EAS)

AF:

0.00155

AC:

AN:

5170

South Asian (SAS)

AF:

0.0921

AC:

445

AN:

4832

European-Finnish (FIN)

AF:

0.231

AC:

2449

AN:

10598

Middle Eastern (MID)

AF:

0.272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.179

AC:

12199

AN:

67962

Other (OTH)

AF:

0.258

AC:

544

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1397

2794

4192

5589

6986

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

390

780

1170

1560

1950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.196

Hom.:

5547

Bravo

AF:

0.298

TwinsUK

AF:

0.185

AC:

687

ALSPAC

AF:

0.176

AC:

680

ESP6500AA

AF:

0.556

AC:

2428

ESP6500EA

AF:

0.187

AC:

1605

ExAC

AF:

0.188

AC:

22643

Asia WGS

AF:

0.0790

AC:

277

AN:

3478

EpiCase

AF:

0.192

EpiControl

AF:

0.194

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 02, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Polycystic kidney disease, adult type

Benign:2

Jul 07, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 02, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Sep 24, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 9521593, 22608885)

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The c.12133A>G, p.Ile4045Val variant was identified in 19.09% of 22171 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015).

Autosomal dominant polycystic kidney disease

Benign:1

Jan 01, 2019

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.042

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.22

T;T

MetaRNN

Benign

0.000086

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.98

N;.

PhyloP100

-0.24

PrimateAI

Benign

0.47

PROVEAN

Benign

0.0

N;N

REVEL

Benign

0.058

Sift

Benign

0.33

T;T

Sift4G

Benign

1.0

T;T

Vest4

0.052

ClinPred

0.0043

GERP RS

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.082

gMVP

0.22

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over