rs3209986

chr16-2090553-G-Achr16-2090553-G-C

Variant summary

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

The NM_001009944.3(PKD1):c.12176C>T(p.Ala4059Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0715 in 1,609,152 control chromosomes in the GnomAD database, including 4,643 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 0.057 ( 360 hom., cov: 34)

Exomes 𝑓: 0.073 ( 4283 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.236

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=0.0025211573).

BP6

Variant 16-2090553-G-A is Benign according to our data. Variant chr16-2090553-G-A is described in ClinVar as [Benign]. Clinvar id is 256915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2090553-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.074 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.12176C>T	p.Ala4059Val	missense_variant	45/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.12176C>T	p.Ala4059Val	missense_variant	45/46	1	NM_001009944.3	P5	P98161-1
PKD1	ENST00000423118.5 linkuse as main transcript	c.12173C>T	p.Ala4058Val	missense_variant	45/46	1		A2	P98161-3
PKD1	ENST00000472577.1 linkuse as main transcript	n.204C>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

AF:

0.0574

AC:

8730

AN:

152174

Hom.:

360

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0147

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0448

Gnomad ASJ

AF:

0.0916

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0593

Gnomad FIN

AF:

0.145

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0758

Gnomad OTH

AF:

0.0497

GnomAD3 exomes

AF:

0.0645

AC:

15475

AN:

239776

Hom.:

648

AF XY:

0.0672

AC XY:

8807

AN XY:

131122

show subpopulations

Gnomad AFR exome

AF:

0.0119

Gnomad AMR exome

AF:

0.0281

Gnomad ASJ exome

AF:

0.102

Gnomad EAS exome

AF:

0.000276

Gnomad SAS exome

AF:

0.0597

Gnomad FIN exome

AF:

0.141

Gnomad NFE exome

AF:

0.0793

Gnomad OTH exome

AF:

0.0674

GnomAD4 exome

AF:

0.0730

AC:

106370

AN:

1456860

Hom.:

4283

Cov.:

AF XY:

0.0729

AC XY:

52833

AN XY:

724778

show subpopulations

Gnomad4 AFR exome

AF:

0.0120

Gnomad4 AMR exome

AF:

0.0290

Gnomad4 ASJ exome

AF:

0.105

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0599

Gnomad4 FIN exome

AF:

0.143

Gnomad4 NFE exome

AF:

0.0767

Gnomad4 OTH exome

AF:

0.0670

GnomAD4 genome

AF:

0.0573

AC:

8725

AN:

152292

Hom.:

360

Cov.:

AF XY:

0.0603

AC XY:

4492

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0147

Gnomad4 AMR

AF:

0.0448

Gnomad4 ASJ

AF:

0.0916

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.0592

Gnomad4 FIN

AF:

0.145

Gnomad4 NFE

AF:

0.0758

Gnomad4 OTH

AF:

0.0491

Alfa

AF:

0.0729

Hom.:

396

Bravo

AF:

0.0464

TwinsUK

AF:

0.0825

AC:

306

ALSPAC

AF:

0.0778

AC:

300

ESP6500AA

AF:

0.0144

AC:

ESP6500EA

AF:

0.0804

AC:

690

ExAC

AF:

0.0657

AC:

7918

Asia WGS

AF:

0.0290

AC:

101

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	Apr 22, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 25, 2017	- -

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.12176C>T, p.Ala4059Val variant was identified in 6.84 % of 7606 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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 29, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.53

Cadd

Benign

7.5

Dann

Benign

0.82

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.64

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.61

N;N

REVEL

Benign

0.091

Sift

Benign

0.20

T;T

Sift4G

Uncertain

0.050

T;T

Polyphen

0.015

B;B

Vest4

0.14

ClinPred

0.00081

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.040

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