rs140869992

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.6598C>T(p.Arg2200Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,568,720 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. R2200H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0090 ( 8 hom., cov: 33)

Exomes 𝑓: 0.014 ( 159 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.44

Publications

14 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=0.0055719614).

BP6

Variant 16-2108569-G-A is Benign according to our data. Variant chr16-2108569-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256990.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 = 0.00903 (1375/152308) while in subpopulation NFE AF = 0.0143 (973/67998). AF 95% confidence interval is 0.0136. There are 8 homozygotes in GnomAd4. There are 604 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.6598C>T	p.Arg2200Cys	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.6598C>T	p.Arg2200Cys	missense_variant	Exon 15 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00904

AC:

1376

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00253

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00681

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0110

Gnomad FIN

AF:

0.00301

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0143

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.0112

AC:

2030

AN:

180444

AF XY:

0.0115

show subpopulations

Gnomad AFR exome

AF:

0.00168

Gnomad AMR exome

AF:

0.00752

Gnomad ASJ exome

AF:

0.0219

Gnomad EAS exome

AF:

0.000148

Gnomad FIN exome

AF:

0.00379

Gnomad NFE exome

AF:

0.0159

Gnomad OTH exome

AF:

0.0133

GnomAD4 exome

AF:

0.0142

AC:

20116

AN:

1416412

Hom.:

159

Cov.:

AF XY:

0.0138

AC XY:

9649

AN XY:

700358

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

32710

American (AMR)

AF:

0.00738

AC:

283

AN:

38368

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

506

AN:

25380

East Asian (EAS)

AF:

0.0000266

AC:

AN:

37632

South Asian (SAS)

AF:

0.0112

AC:

923

AN:

82066

European-Finnish (FIN)

AF:

0.00432

AC:

210

AN:

48576

Middle Eastern (MID)

AF:

0.0115

AC:

AN:

4086

European-Non Finnish (NFE)

AF:

0.0158

AC:

17259

AN:

1089098

Other (OTH)

AF:

0.0138

AC:

809

AN:

58496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1131

2263

3394

4526

5657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

676

1352

2028

2704

3380

<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:

0.00903

AC:

1375

AN:

152308

Hom.:

Cov.:

AF XY:

0.00811

AC XY:

604

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00253

AC:

105

AN:

41576

American (AMR)

AF:

0.00680

AC:

104

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.0110

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00301

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0143

AC:

973

AN:

67998

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

136

204

272

340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00864

Hom.:

Bravo

AF:

0.00905

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.0205

AC:

ESP6500AA

AF:

0.00264

AC:

ESP6500EA

AF:

0.0138

AC:

113

ExAC

AF:

0.00913

AC:

1005

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 16, 2025

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: frequency -

not provided

Benign:3

Dec 02, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22383692, 17574468, 18791038, 12842373, 18837007, 26632257, 27499327, 32823016) -

Jun 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

- -

Polycystic kidney disease, adult type

Benign:2

Dec 02, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 15, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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.Arg2200Cys variant was identified in 10 of 678 proband chromosomes (frequency: 0.015) from Chinese and North American individuals or families with ADPKD (Liu 2015, Garcia-Gonzalez 2007, Rossetti, Tan 2009). The variant was identified with co-occurring pathogenic PKD1 variants (N116fsX and IVS24+5G>C), in 2 individuals who each had 5-7 identified variants, increasing the likelihood that the p.Arg2200Cys variant does not have clinical significance (Garcia-Gonzalez 2007). The variant was also identified in dbSNP (ID: rs140869992) as â€šÃ„ÃºNAâ€šÃ„Ã¹, ADPKD Mutation Database (classification â€šÃ„Ãºlikely neutralâ€šÃ„Ã¹), in the 1000 Genomes Project in 36 of 5000 chromosomes (frequency: 0.0072), HAP-MAP populations: EUR in 17 of 1006 chromosomes (frequency: 0.0169), SAS in 15 of 978 chromosomes (frequency: 0.0153), AMR in 4 of 694 chromosomes (frequency: 0.0058), in NHLBI GO Exome Sequencing Project in 113 of 8182 (frequency: 0.0138) European American alleles, in 11 of 4170 African American alleles (frequency: 0.0026), and in all populations in the Exome Aggregation Consortium database (March 14 2016) in 755 of 42138 alleles (frequency 0.018) or in European (Non-Finnish) in 534 (1 homozygous) of 20712 (frequency: 0.0258), other populations in 6 of 314 (frequency: 0.0191), South Asian in 160 (1 homozygous) of 10450 (frequency: 0.0015), Latino in 36 of 2818 (frequency: 0.0128), European (Finnish) in 7 of 1456 (frequency: 0.0048), African in 11 of 3512 (frequency: 0.0003), and East Asian in 1 of 2876 alleles (frequency: 00003), increasing the likelihood this could be a low frequency benign variant. The p.Arg2200residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Autosomal dominant polycystic kidney disease

Benign:1

Jan 01, 2019

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

PKD1-related disorder

Benign:1

Sep 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

0.22

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.097

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.27

LIST_S2

Uncertain

0.87

D;D

MetaRNN

Benign

0.0056

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

1.4

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.23

Sift

Benign

0.046

D;D

Sift4G

Uncertain

0.028

D;D

Polyphen

1.0

D;D

Vest4

0.39

ClinPred

0.012

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.087

gMVP

0.50

Mutation Taster

=73/27

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

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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