rs116092985

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001009944.3(PKD1):c.4195T>C(p.Trp1399Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0843 in 1,597,052 control chromosomes in the GnomAD database, including 6,826 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.078 ( 563 hom., cov: 33)

Exomes 𝑓: 0.085 ( 6263 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.237

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:

PKD1 (HGNC:):

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=0.0042101443).

BP6

Variant 16-2110972-A-G is Benign according to our data. Variant chr16-2110972-A-G is described in ClinVar as [Benign]. Clinvar id is 256962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2110972-A-G is described in Lovd as [Benign]. Variant chr16-2110972-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.4195T>C	p.Trp1399Arg	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.4195T>C	p.Trp1399Arg	missense_variant	15/46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0778

AC:

11846

AN:

152206

Hom.:

563

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0505

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.0848

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0261

Gnomad FIN

AF:

0.0760

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.0975

Gnomad OTH

AF:

0.0942

GnomAD3 exomes

AF:

0.0650

AC:

15796

AN:

243130

Hom.:

783

AF XY:

0.0657

AC XY:

8696

AN XY:

132400

show subpopulations

Gnomad AFR exome

AF:

0.0404

Gnomad AMR exome

AF:

0.0545

Gnomad ASJ exome

AF:

0.135

Gnomad EAS exome

AF:

0.0000551

Gnomad SAS exome

AF:

0.0269

Gnomad FIN exome

AF:

0.0677

Gnomad NFE exome

AF:

0.0850

Gnomad OTH exome

AF:

0.0930

GnomAD4 exome

AF:

0.0850

AC:

122750

AN:

1444728

Hom.:

6263

Cov.:

AF XY:

0.0839

AC XY:

60294

AN XY:

718702

show subpopulations

Gnomad4 AFR exome

AF:

0.0468

Gnomad4 AMR exome

AF:

0.0596

Gnomad4 ASJ exome

AF:

0.139

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0301

Gnomad4 FIN exome

AF:

0.0684

Gnomad4 NFE exome

AF:

0.0937

Gnomad4 OTH exome

AF:

0.0855

GnomAD4 genome

AF:

0.0778

AC:

11849

AN:

152324

Hom.:

563

Cov.:

AF XY:

0.0741

AC XY:

5521

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0505

Gnomad4 AMR

AF:

0.0847

Gnomad4 ASJ

AF:

0.151

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0261

Gnomad4 FIN

AF:

0.0760

Gnomad4 NFE

AF:

0.0976

Gnomad4 OTH

AF:

0.0932

Alfa

AF:

0.0814

Hom.:

242

Bravo

AF:

0.0795

TwinsUK

AF:

0.0963

AC:

357

ALSPAC

AF:

0.0929

AC:

358

ExAC

AF:

0.0662

AC:

8003

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2019	This variant is associated with the following publications: (PMID: 24374109) -

Polycystic kidney disease, adult type

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 07, 2020

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1, p.Trp1399Arg variant was identified in 6.7% of 11722 control alleles in the Exome Aggregation Consortium (March 14, 2016). This variant was identified by our laboratory with a co-occurring pathogenic PKD1 variant (c.11798_11810del, p.Leu3933ArgfsX8), in a patient with PKD increasing the likelihood that the p.Ala3512Val variant does not have clinical significance. 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

Benign, criteria provided, single submitter

research

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

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.68

CADD

Benign

4.9

DANN

Benign

0.44

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.055

T;T

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.6

N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

1.1

N;N

REVEL

Benign

0.091

Sift

Benign

0.36

T;T

Sift4G

Benign

0.69

T;T

Polyphen

0.0

B;B

Vest4

0.021

MutPred

0.60

Loss of catalytic residue at W1399 (P = 0.0152);Loss of catalytic residue at W1399 (P = 0.0152);

ClinPred

0.0042

GERP RS

3.4

Varity_R

0.057

gMVP

0.33

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