rs143690392

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001009944.3(PKD1):c.4018C>T(p.Arg1340Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,611,100 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1340Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0031 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 13 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.303

Publications

11 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=0.036586612).

BP6

Variant 16-2111149-G-A is Benign according to our data. Variant chr16-2111149-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00308 (469/152322) while in subpopulation NFE AF = 0.00435 (296/68012). AF 95% confidence interval is 0.00394. There are 2 homozygotes in GnomAd4. There are 199 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.4018C>T	p.Arg1340Trp	missense_variant	Exon 15 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.4018C>T	p.Arg1340Trp	missense_variant	Exon 15 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00307

AC:

467

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00442

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00435

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00256

AC:

631

AN:

246614

AF XY:

0.00244

show subpopulations

Gnomad AFR exome

AF:

0.00237

Gnomad AMR exome

AF:

0.000987

Gnomad ASJ exome

AF:

0.000804

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00472

Gnomad NFE exome

AF:

0.00390

Gnomad OTH exome

AF:

0.00265

GnomAD4 exome

AF:

0.00364

AC:

5306

AN:

1458778

Hom.:

Cov.:

AF XY:

0.00354

AC XY:

2568

AN XY:

725756

show subpopulations

African (AFR)

AF:

0.00215

AC:

AN:

33418

American (AMR)

AF:

0.000850

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.000881

AC:

AN:

26110

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.00386

AC:

201

AN:

52110

Middle Eastern (MID)

AF:

0.000650

AC:

AN:

4614

European-Non Finnish (NFE)

AF:

0.00431

AC:

4787

AN:

1111732

Other (OTH)

AF:

0.00292

AC:

176

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

352

704

1055

1407

1759

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

344

516

688

860

<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:

0.00308

AC:

469

AN:

152322

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

199

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

41572

American (AMR)

AF:

0.00281

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00442

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00435

AC:

296

AN:

68012

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

108

135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00358

Hom.:

Bravo

AF:

0.00258

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00408

AC:

ExAC

AF:

0.00241

AC:

291

EpiCase

AF:

0.00436

EpiControl

AF:

0.00296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 21, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 10, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22008521, 26489027, 11967008, 22995991, 27499327) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PKD1: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Polycystic kidney disease, adult type

Benign:2

Apr 08, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 03, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jun 18, 2025

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PKD1 c.4018C>T (p.Arg1340Trp) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.0026 in 246614 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in PKD1 causing PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease phenotype. c.4018C>T has been observed in individual(s) affected with Polycystic Kidney Disease without strong evidence for causality (Carrera_2016, Rasouly_2019, Rossetti_2002). These report(s) do not provide unequivocal conclusions about association of the variant with PKD1-related Polycystic Kidney Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27499327, 30476936, 11967008). ClinVar contains an entry for this variant (Variation ID: 256960). Based on the evidence outlined above, the variant was classified as likely benign. -

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 PKD1 p.Arg1340Trp variant was identified in 5 of 328 proband chromosomes (frequency: 0.015) from individuals or families with ADPKD (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2002, Rossetti 2007). The variant was also identified in dbSNP (ID: rs143690392) as â€šÃ„ÃºNAâ€šÃ„Ã¹, and ADPKD Mutation Database (as likely neutral). This variant was identified in the 1000 Genomes Project in 10 of 5000 chromosomes (freq. 0.002), the NHLBI GO Exome Sequencing Project in 35 of 8582 European American alleles (freq. 0.004) and in 5 of 4374 African American alleles (freq. 0.001), the Exome Aggregation Consortium database (August 8, 2016) in 286 (1 homozygous) of 116868 chromosomes (freq. 0.002) in the following populations Finnish in 36 of 6204 chromosomes (freq. 0.006), European (Non-Finnish) in 220 of 63994 chromosomes (freq. 0.003), other in 2 of 838 chromosomes (freq. 0.002), African in 21 of 9516 chromosomes (freq. 0.002), Latino in 6 of 11372 chromosomes (freq. 0.0005), and South Asian in 1 of 16460 chromosomes (freq. 0.00006), but was not seen in East Asian populations, increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant was not identified in Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. The p.Arg1340 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and 1 in 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a difference in splicing. The variant was identified with a co-occurring pathogenic PKD1 variant p.Leu56ProfsX60, increasing the likelihood that the p.Arg2191His variant does not have clinical significance. In addition, the variant was classified as â€šÃ„Ãºa known exonic polymorphismâ€šÃ„Ã¹ in multiple studies (Rossetti 2012, Bataille 2011). In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

PKD1-related disorder

Benign:1

Aug 05, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

0.066

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

5.1

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.29

T;T

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.037

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L

PhyloP100

-0.30

PrimateAI

Benign

0.19

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.29

Sift

Benign

0.16

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.032

B;B

Vest4

0.71

MVP

0.99

ClinPred

0.0025

GERP RS

-7.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.056

gMVP

0.38

Mutation Taster

=67/33

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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