16-2099651-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001009944.3(PKD1):c.10043G>A(p.Arg3348Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000594 in 1,591,192 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3348W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 1 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 5.44

Publications

5 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056121916).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000606 (872/1438860) while in subpopulation NFE AF = 0.000739 (820/1109014). AF 95% confidence interval is 0.000697. There are 1 homozygotes in GnomAdExome4. There are 420 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.10043G>A	p.Arg3348Gln	missense_variant	Exon 30 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 link	c.10043G>A	p.Arg3348Gln	missense_variant	Exon 30 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000305

AC:

AN:

186804

AF XY:

0.000264

show subpopulations

Gnomad AFR exome

AF:

0.000508

Gnomad AMR exome

AF:

0.000168

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000687

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000523

Gnomad OTH exome

AF:

0.000397

GnomAD4 exome

AF:

0.000606

AC:

872

AN:

1438860

Hom.:

Cov.:

AF XY:

0.000587

AC XY:

420

AN XY:

715634

show subpopulations

African (AFR)

AF:

0.000482

AC:

AN:

33208

American (AMR)

AF:

0.000204

AC:

AN:

44148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26028

East Asian (EAS)

AF:

0.00

AC:

AN:

39368

South Asian (SAS)

AF:

0.0000352

AC:

AN:

85128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.000739

AC:

820

AN:

1109014

Other (OTH)

AF:

0.000401

AC:

AN:

59878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

128

171

214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.000479

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

41578

American (AMR)

AF:

0.000261

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000583

Hom.:

Bravo

AF:

0.000450

ESP6500AA

AF:

0.000984

AC:

ESP6500EA

AF:

0.000644

AC:

ExAC

AF:

0.000255

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Sep 30, 2016

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 26, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PKD1 c.10043G>A (p.Arg3348Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 186804 control chromosomes, predominantly at a frequency of 0.00052 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in PKD1 causing Polycystic Kidney Disease 1 phenotype (0.0005), suggesting that the variant could be a benign polymorphism found primarily in populations of Non-Finnish European origin, yet this should be interpreted with caution due to the presence of the PKD1 pseudogene. c.10043G>A has been reported in the literature in multiple individuals affected with Polycystic Kidney Disease 1 (e.g. Bataille_2011, Chang_2013, Cornec-LeGall_2013, Carrera_2016, Bullich_2018). However, this also includes cases where it was found in individuals with other PKD1 variants, including a truncating variant (PKD1 c.1960C>T, p.Arg654X; Chang_2013) and a pathogenic variant in PKD2 (PKD2 c.1094+1G>A; Carrera_2016), providing supporting evidence for a benign role. Thus, these reports do not provide unequivocal conclusions about association of the variant with Polycystic Kidney Disease 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26139440, 22008521, 29801666, 27499327, 23985799, 23431072). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Polycystic kidney disease, adult type

Uncertain:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 16, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:2

Dec 12, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in unrelated patients with polycystic kidney disease in published literature (Bataille et al., 2011; Chang et al., 2013; Cornec-Le Gall et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23431072, 22008521, 23985799, 29801666, 31514750) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

PKD1-related disorder

Uncertain:1

Jun 17, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PKD1 c.10043G>A variant is predicted to result in the amino acid substitution p.Arg3348Gln. This variant has been reported as a variant of uncertain significance in multiple individuals with polycystic kidney disease (see, for example, Chang et al. 2013. PubMed ID: 23985799; Cornec-Le Gall et al. 2013. PubMed ID: 23431072; Carrera et al. 2016. PubMed ID: 27499327). However, this variant is also reported in 0.065% of alleles in individuals of African descent in gnomAD, which is higher than expected for a fully penetrant pathogenic variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.46

T;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.056

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.6

M;M

PhyloP100

5.4

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.7

D;D

REVEL

Benign

0.29

Sift

Uncertain

0.013

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.44

MVP

0.85

ClinPred

0.068

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.35

gMVP

0.61

Mutation Taster

=50/50

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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