chr16-2102386-A-G

Position:

chr16-2102386-A-G

Variant summary

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

The NM_001009944.3(PKD1):c.9196T>C(p.Phe3066Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,555,320 control chromosomes in the GnomAD database, including 27,908 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 6324 hom., cov: 33)

Exomes 𝑓: 0.16 ( 21584 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.610

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=6.9981813E-4).

BP6

Variant 16-2102386-A-G is Benign according to our data. Variant chr16-2102386-A-G is described in ClinVar as [Benign]. Clinvar id is 257040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.9196T>C	p.Phe3066Leu	missense_variant	25/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.9196T>C	p.Phe3066Leu	missense_variant	25/46	1	NM_001009944.3	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.246

AC:

37355

AN:

151628

Hom.:

6305

Cov.:

show subpopulations

Gnomad AFR

AF:

0.481

Gnomad AMI

AF:

0.0978

Gnomad AMR

AF:

0.184

Gnomad ASJ

AF:

0.231

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0702

Gnomad FIN

AF:

0.188

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.162

Gnomad OTH

AF:

0.232

GnomAD3 exomes

AF:

0.156

AC:

24737

AN:

158300

Hom.:

2754

AF XY:

0.149

AC XY:

12541

AN XY:

84164

show subpopulations

Gnomad AFR exome

AF:

0.503

Gnomad AMR exome

AF:

0.119

Gnomad ASJ exome

AF:

0.233

Gnomad EAS exome

AF:

0.000260

Gnomad SAS exome

AF:

0.0731

Gnomad FIN exome

AF:

0.184

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.164

AC:

229760

AN:

1403576

Hom.:

21584

Cov.:

AF XY:

0.160

AC XY:

111113

AN XY:

693318

show subpopulations

Gnomad4 AFR exome

AF:

0.495

Gnomad4 AMR exome

AF:

0.127

Gnomad4 ASJ exome

AF:

0.236

Gnomad4 EAS exome

AF:

0.000436

Gnomad4 SAS exome

AF:

0.0747

Gnomad4 FIN exome

AF:

0.181

Gnomad4 NFE exome

AF:

0.164

Gnomad4 OTH exome

AF:

0.177

GnomAD4 genome

AF:

0.247

AC:

37418

AN:

151744

Hom.:

6324

Cov.:

AF XY:

0.241

AC XY:

17870

AN XY:

74210

show subpopulations

Gnomad4 AFR

AF:

0.482

Gnomad4 AMR

AF:

0.184

Gnomad4 ASJ

AF:

0.231

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.0697

Gnomad4 FIN

AF:

0.188

Gnomad4 NFE

AF:

0.162

Gnomad4 OTH

AF:

0.229

Alfa

AF:

0.156

Hom.:

720

Bravo

AF:

0.259

ESP6500AA

AF:

0.315

AC:

1321

ESP6500EA

AF:

0.0838

AC:

698

ExAC

AF:

0.121

AC:

12389

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Polycystic kidney disease, adult type

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 08, 2020

- -

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 25, 2019

This variant is associated with the following publications: (PMID: 10854095) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

9.2

DANN

Benign

0.86

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.49

T;T

MetaRNN

Benign

0.00070

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

P;P

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.98

N;N

REVEL

Benign

0.085

Sift

Benign

0.66

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.21

B;P

Vest4

0.14

MutPred

0.44

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

ClinPred

0.0099

GERP RS

-2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.040

gMVP

0.43

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