chr16-2090553-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely 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/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.236

Publications

29 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant polycystic kidney disease
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
polycystic kidney disease 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
autosomal recessive polycystic kidney disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Caroli disease
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

PKD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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/Likely_benign. ClinVar VariationId is 256915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.12176C>T	p.Ala4059Val	missense_variant	Exon 45 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PKD1	ENST00000262304.9 link	c.12176C>T	p.Ala4059Val	missense_variant	Exon 45 of 46	1	NM_001009944.3	ENSP00000262304.4
PKD1	ENST00000423118.5 link	c.12173C>T	p.Ala4058Val	missense_variant	Exon 45 of 46	1		ENSP00000399501.1
PKD1	ENST00000472577.1 link	n.204C>T		non_coding_transcript_exon_variant	Exon 2 of 3	2
PKD1	ENST00000564313.1 link	n.*212C>T		downstream_gene_variant		4

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

GnomAD2 exomes

AF:

0.0645

AC:

15475

AN:

239776

AF XY:

0.0672

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 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

African (AFR)

AF:

0.0120

AC:

400

AN:

33438

American (AMR)

AF:

0.0290

AC:

1295

AN:

44580

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

2736

AN:

26114

East Asian (EAS)

AF:

0.000202

AC:

AN:

39658

South Asian (SAS)

AF:

0.0599

AC:

5164

AN:

86144

European-Finnish (FIN)

AF:

0.143

AC:

7101

AN:

49610

Middle Eastern (MID)

AF:

0.0617

AC:

353

AN:

5724

European-Non Finnish (NFE)

AF:

0.0767

AC:

85273

AN:

1111286

Other (OTH)

AF:

0.0670

AC:

4040

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

6281

12562

18842

25123

31404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3116

6232

9348

12464

15580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0573

AC:

8725

AN:

152292

Hom.:

360

Cov.:

AF XY:

0.0603

AC XY:

4492

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0147

AC:

610

AN:

41572

American (AMR)

AF:

0.0448

AC:

685

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0916

AC:

318

AN:

3472

East Asian (EAS)

AF:

0.000773

AC:

AN:

5176

South Asian (SAS)

AF:

0.0592

AC:

286

AN:

4832

European-Finnish (FIN)

AF:

0.145

AC:

1543

AN:

10608

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0758

AC:

5152

AN:

68006

Other (OTH)

AF:

0.0491

AC:

104

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

414

829

1243

1658

2072

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0723

Hom.:

539

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/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 02, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Polycystic kidney disease, adult type

Benign:2

Apr 22, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 25, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Aug 29, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jan 01, 2019

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

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

(source)

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;.

PhyloP100

0.24

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

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

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over