rs140869992

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

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:11

Conservation

PhyloP100: 1.44

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 256990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2108569-G-A is described in Lovd as [Benign]. Variant chr16-2108569-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1375 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.6598C>T	p.Arg2200Cys	missense_variant	15/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.6598C>T	p.Arg2200Cys	missense_variant	15/46	1	NM_001009944.3	ENSP00000262304	P5	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

GnomAD3 exomes

AF:

0.0112

AC:

2030

AN:

180444

Hom.:

AF XY:

0.0115

AC XY:

1128

AN XY:

97686

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 SAS exome

AF:

0.0124

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

Gnomad4 AFR exome

AF:

0.00238

Gnomad4 AMR exome

AF:

0.00738

Gnomad4 ASJ exome

AF:

0.0199

Gnomad4 EAS exome

AF:

0.0000266

Gnomad4 SAS exome

AF:

0.0112

Gnomad4 FIN exome

AF:

0.00432

Gnomad4 NFE exome

AF:

0.0158

Gnomad4 OTH exome

AF:

0.0138

GnomAD4 genome

AF:

0.00903

AC:

1375

AN:

152308

Hom.:

Cov.:

AF XY:

0.00811

AC XY:

604

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00253

Gnomad4 AMR

AF:

0.00680

Gnomad4 ASJ

AF:

0.0245

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0110

Gnomad4 FIN

AF:

0.00301

Gnomad4 NFE

AF:

0.0143

Gnomad4 OTH

AF:

0.00946

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:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2019	This variant is associated with the following publications: (PMID: 22383692, 17574468, 18791038, 12842373, 18837007, 26632257, 27499327, 32823016) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PKD1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease, adult type

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 02, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 15, 2022	- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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

Likely benign, criteria provided, single submitter

research

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

Jan 01, 2019

- -

PKD1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 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

0.22

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Benign

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

MutationTaster

Benign

1.0

N;N

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over