rs146887330

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.3502C>T(p.Pro1168Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,574,942 control chromosomes in the GnomAD database, including 312 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1168A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 21 hom., cov: 33)

Exomes 𝑓: 0.018 ( 291 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.458

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=0.0032174885).

BP6

Variant 16-2111665-G-A is Benign according to our data. Variant chr16-2111665-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2111665-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (2005/152250) while in subpopulation NFE AF= 0.0195 (1327/67990). AF 95% confidence interval is 0.0186. There are 21 homozygotes in gnomad4. There are 988 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2005 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.3502C>T	p.Pro1168Ser	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.3502C>T	p.Pro1168Ser	missense_variant	15/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

2005

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00290

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.0350

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0195

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.0143

AC:

2619

AN:

183752

Hom.:

AF XY:

0.0146

AC XY:

1444

AN XY:

99168

show subpopulations

Gnomad AFR exome

AF:

0.00280

Gnomad AMR exome

AF:

0.00449

Gnomad ASJ exome

AF:

0.0229

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00901

Gnomad FIN exome

AF:

0.0309

Gnomad NFE exome

AF:

0.0193

Gnomad OTH exome

AF:

0.00992

GnomAD4 exome

AF:

0.0182

AC:

25844

AN:

1422692

Hom.:

291

Cov.:

AF XY:

0.0177

AC XY:

12460

AN XY:

704446

show subpopulations

Gnomad4 AFR exome

AF:

0.00251

Gnomad4 AMR exome

AF:

0.00449

Gnomad4 ASJ exome

AF:

0.0198

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00934

Gnomad4 FIN exome

AF:

0.0285

Gnomad4 NFE exome

AF:

0.0202

Gnomad4 OTH exome

AF:

0.0134

GnomAD4 genome

AF:

0.0132

AC:

2005

AN:

152250

Hom.:

Cov.:

AF XY:

0.0133

AC XY:

988

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00289

Gnomad4 AMR

AF:

0.00320

Gnomad4 ASJ

AF:

0.0190

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00684

Gnomad4 FIN

AF:

0.0350

Gnomad4 NFE

AF:

0.0195

Gnomad4 OTH

AF:

0.0162

Alfa

AF:

0.0128

Hom.:

Bravo

AF:

0.0107

ESP6500AA

AF:

0.00376

AC:

ESP6500EA

AF:

0.0142

AC:

120

ExAC

AF:

0.0112

AC:

1316

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Polycystic kidney disease, adult type

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 16, 2020	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2019	This variant is associated with the following publications: (PMID: 18640754) -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

7.3

DANN

Benign

0.93

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.95

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.78

N;N

REVEL

Benign

0.068

Sift

Benign

0.38

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.21

B;P

Vest4

0.092

ClinPred

0.0030

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.074

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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