NM_001009944.3:c.4195T>C

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.4195T>C(p.Trp1399Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0843 in 1,597,052 control chromosomes in the GnomAD database, including 6,826 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1399Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.078 ( 563 hom., cov: 33)

Exomes 𝑓: 0.085 ( 6263 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.237

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=0.0042101443).

BP6

Variant 16-2110972-A-G is Benign according to our data. Variant chr16-2110972-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.4195T>C	p.Trp1399Arg	missense_variant	Exon 15 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.4195T>C	p.Trp1399Arg	missense_variant	Exon 15 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0778

AC:

11846

AN:

152206

Hom.:

563

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0505

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.0848

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0261

Gnomad FIN

AF:

0.0760

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.0975

Gnomad OTH

AF:

0.0942

GnomAD2 exomes

AF:

0.0650

AC:

15796

AN:

243130

AF XY:

0.0657

show subpopulations

Gnomad AFR exome

AF:

0.0404

Gnomad AMR exome

AF:

0.0545

Gnomad ASJ exome

AF:

0.135

Gnomad EAS exome

AF:

0.0000551

Gnomad FIN exome

AF:

0.0677

Gnomad NFE exome

AF:

0.0850

Gnomad OTH exome

AF:

0.0930

GnomAD4 exome

AF:

0.0850

AC:

122750

AN:

1444728

Hom.:

6263

Cov.:

AF XY:

0.0839

AC XY:

60294

AN XY:

718702

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0468

AC:

1554

AN:

33210

American (AMR)

AF:

0.0596

AC:

2648

AN:

44394

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

3591

AN:

25860

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0301

AC:

2587

AN:

85944

European-Finnish (FIN)

AF:

0.0684

AC:

3548

AN:

51884

Middle Eastern (MID)

AF:

0.147

AC:

614

AN:

4174

European-Non Finnish (NFE)

AF:

0.0937

AC:

103098

AN:

1099796

Other (OTH)

AF:

0.0855

AC:

5108

AN:

59766

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.372

Heterozygous variant carriers

4559

9117

13676

18234

22793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3656

7312

10968

14624

18280

<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:

0.0778

AC:

11849

AN:

152324

Hom.:

563

Cov.:

AF XY:

0.0741

AC XY:

5521

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0505

AC:

2098

AN:

41584

American (AMR)

AF:

0.0847

AC:

1295

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

523

AN:

3470

East Asian (EAS)

AF:

0.000772

AC:

AN:

5184

South Asian (SAS)

AF:

0.0261

AC:

126

AN:

4828

European-Finnish (FIN)

AF:

0.0760

AC:

808

AN:

10626

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0976

AC:

6635

AN:

68014

Other (OTH)

AF:

0.0932

AC:

197

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

529

1058

1586

2115

2644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<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:

0.0814

Hom.:

242

Bravo

AF:

0.0795

TwinsUK

AF:

0.0963

AC:

357

ALSPAC

AF:

0.0929

AC:

358

ExAC

AF:

0.0662

AC:

8003

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 01, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 04, 2025

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Dec 30, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24374109) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Polycystic kidney disease, adult type

Benign:1

Jul 07, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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 PKD1, p.Trp1399Arg variant was identified in 6.7% of 11722 control alleles in the Exome Aggregation Consortium (March 14, 2016). This variant was identified by our laboratory with a co-occurring pathogenic PKD1 variant (c.11798_11810del, p.Leu3933ArgfsX8), in a patient with PKD increasing the likelihood that the p.Ala3512Val variant does not have clinical significance. 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

0.044

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.68

CADD

Benign

4.9

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.055

T;T

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.6

N;N

PhyloP100

0.24

PrimateAI

Benign

0.22

PROVEAN

Benign

1.1

N;N

REVEL

Benign

0.091

Sift

Benign

0.36

T;T

Sift4G

Benign

0.69

T;T

Polyphen

0.0

B;B

Vest4

0.021

MutPred

0.60

Loss of catalytic residue at W1399 (P = 0.0152);Loss of catalytic residue at W1399 (P = 0.0152);

ClinPred

0.0042

GERP RS

3.4

Varity_R

0.057

gMVP

0.33

Mutation Taster

=100/0

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