16-2090679-T-C

Position:

chr16-2090679-T-C

Variant summary

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

The ENST00000262304.9(PKD1):c.12133A>G(p.Ile4045Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,611,784 control chromosomes in the GnomAD database, including 37,119 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 0.29 ( 9035 hom., cov: 34)

Exomes 𝑓: 0.18 ( 28084 hom. )

Consequence

PKD1
ENST00000262304.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.239

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=8.577714E-5).

BP6

Variant 16-2090679-T-C is Benign according to our data. Variant chr16-2090679-T-C is described in ClinVar as [Benign]. Clinvar id is 256913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2090679-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.573 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.12133A>G	p.Ile4045Val	missense_variant	44/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.12133A>G	p.Ile4045Val	missense_variant	44/46	1	NM_001009944.3	ENSP00000262304.4	P98161-1
PKD1	ENST00000423118.5 linkuse as main transcript	c.12130A>G	p.Ile4044Val	missense_variant	44/46	1		ENSP00000399501.1	P98161-3
PKD1	ENST00000472577.1 linkuse as main transcript	n.161A>G		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.288

AC:

43759

AN:

152030

Hom.:

9006

Cov.:

show subpopulations

Gnomad AFR

AF:

0.579

Gnomad AMI

AF:

0.0976

Gnomad AMR

AF:

0.203

Gnomad ASJ

AF:

0.254

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0922

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.179

Gnomad OTH

AF:

0.261

GnomAD3 exomes

AF:

0.181

AC:

44565

AN:

245684

Hom.:

5904

AF XY:

0.175

AC XY:

23389

AN XY:

133890

show subpopulations

Gnomad AFR exome

AF:

0.581

Gnomad AMR exome

AF:

0.122

Gnomad ASJ exome

AF:

0.255

Gnomad EAS exome

AF:

0.000275

Gnomad SAS exome

AF:

0.0920

Gnomad FIN exome

AF:

0.222

Gnomad NFE exome

AF:

0.183

Gnomad OTH exome

AF:

0.190

GnomAD4 exome

AF:

0.181

AC:

263811

AN:

1459636

Hom.:

28084

Cov.:

AF XY:

0.177

AC XY:

128525

AN XY:

726110

show subpopulations

Gnomad4 AFR exome

AF:

0.585

Gnomad4 AMR exome

AF:

0.131

Gnomad4 ASJ exome

AF:

0.261

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0950

Gnomad4 FIN exome

AF:

0.221

Gnomad4 NFE exome

AF:

0.179

Gnomad4 OTH exome

AF:

0.195

GnomAD4 genome

AF:

0.288

AC:

43838

AN:

152148

Hom.:

9035

Cov.:

AF XY:

0.285

AC XY:

21189

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.579

Gnomad4 AMR

AF:

0.203

Gnomad4 ASJ

AF:

0.254

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.0921

Gnomad4 FIN

AF:

0.231

Gnomad4 NFE

AF:

0.179

Gnomad4 OTH

AF:

0.258

Alfa

AF:

0.190

Hom.:

3377

Bravo

AF:

0.298

TwinsUK

AF:

0.185

AC:

687

ALSPAC

AF:

0.176

AC:

680

ESP6500AA

AF:

0.556

AC:

2428

ESP6500EA

AF:

0.187

AC:

1605

ExAC

AF:

0.188

AC:

22643

Asia WGS

AF:

0.0790

AC:

277

AN:

3478

EpiCase

AF:

0.192

EpiControl

AF:

0.194

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic kidney disease, adult type

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 02, 2017	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2019	This variant is associated with the following publications: (PMID: 9521593, 22608885) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The c.12133A>G, p.Ile4045Val variant was identified in 19.09% of 22171 control alleles in the Exome Aggregation Consortium (March 14, 2016). 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

0.071

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.042

DANN

Benign

0.53

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.22

T;T

MetaRNN

Benign

0.000086

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.98

N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.47

PROVEAN

Benign

0.0

N;N

REVEL

Benign

0.058

Sift

Benign

0.33

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0020

B;B

Vest4

0.052

ClinPred

0.0043

GERP RS

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.082

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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