rs148164067

Positions:

chr16-2110621-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001009944.3(PKD1):c.4546G>A(p.Ala1516Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00673 in 1,610,296 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0069 ( 36 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.71

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=0.010074973).

BP6

Variant 16-2110621-C-T is Benign according to our data. Variant chr16-2110621-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2110621-C-T is described in Lovd as [Benign]. Variant chr16-2110621-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00498 (758/152310) while in subpopulation NFE AF= 0.00766 (521/68018). AF 95% confidence interval is 0.00712. There are 2 homozygotes in gnomad4. There are 363 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 758 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.4546G>A	p.Ala1516Thr	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.4546G>A	p.Ala1516Thr	missense_variant	15/46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00499

AC:

759

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00828

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00766

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00576

AC:

1430

AN:

248178

Hom.:

AF XY:

0.00584

AC XY:

789

AN XY:

135060

show subpopulations

Gnomad AFR exome

AF:

0.000818

Gnomad AMR exome

AF:

0.000869

Gnomad ASJ exome

AF:

0.0156

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00435

Gnomad FIN exome

AF:

0.00919

Gnomad NFE exome

AF:

0.00775

Gnomad OTH exome

AF:

0.00627

GnomAD4 exome

AF:

0.00691

AC:

10077

AN:

1457986

Hom.:

Cov.:

AF XY:

0.00687

AC XY:

4981

AN XY:

725228

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.0160

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00447

Gnomad4 FIN exome

AF:

0.00976

Gnomad4 NFE exome

AF:

0.00742

Gnomad4 OTH exome

AF:

0.00655

GnomAD4 genome

AF:

0.00498

AC:

758

AN:

152310

Hom.:

Cov.:

AF XY:

0.00488

AC XY:

363

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00135

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00414

Gnomad4 FIN

AF:

0.00828

Gnomad4 NFE

AF:

0.00766

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00730

Hom.:

Bravo

AF:

0.00414

ESP6500AA

AF:

0.00160

AC:

ESP6500EA

AF:

0.00711

AC:

ExAC

AF:

0.00605

AC:

731

EpiCase

AF:

0.00780

EpiControl

AF:

0.00670

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2020	This variant is associated with the following publications: (PMID: 17574468, 18640754, 22383692, 18837007, 22008521) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	PKD1: BP4, BS2 -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 04, 2020	- -

Polycystic kidney disease, adult type

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 01, 2020

- -

PKD1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 01, 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

0.070

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.0030

DANN

Benign

0.81

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.29

T;T

M_CAP

Benign

0.066

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.10

N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

0.57

N;N

REVEL

Benign

0.017

Sift

Benign

0.51

T;T

Sift4G

Benign

0.51

T;T

Polyphen

0.083

B;B

Vest4

0.15

MVP

0.61

ClinPred

0.0043

GERP RS

-8.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.021

gMVP

0.22

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