rs771382752

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS1

The NM_001009944.3(PKD1):c.8305C>T(p.Leu2769Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000839 in 1,609,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 9.52

Publications

0 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 -7 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_001009944.3

BP4

Computational evidence support a benign effect (MetaRNN=0.04360816).

BP6

Variant 16-2103752-G-A is Benign according to our data. Variant chr16-2103752-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 440092.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000857 (125/1458146) while in subpopulation AMR AF = 0.00251 (112/44702). AF 95% confidence interval is 0.00213. There are 0 homozygotes in GnomAdExome4. There are 50 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.8305C>T	p.Leu2769Phe	missense_variant	Exon 23 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.8305C>T	p.Leu2769Phe	missense_variant	Exon 23 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes

AF:

0.0000659

AC:

AN:

151740

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.000462

AC:

114

AN:

246822

AF XY:

0.000304

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00322

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000165

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000857

AC:

125

AN:

1458146

Hom.:

Cov.:

AF XY:

0.0000689

AC XY:

AN XY:

725370

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33402

American (AMR)

AF:

0.00251

AC:

112

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.000227

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111692

Other (OTH)

AF:

0.0000166

AC:

AN:

60176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000659

AC:

AN:

151740

Hom.:

Cov.:

AF XY:

0.0000945

AC XY:

AN XY:

74074

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41288

American (AMR)

AF:

0.000524

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5044

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67946

Other (OTH)

AF:

0.000481

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000130

Hom.:

Bravo

AF:

0.000208

ExAC

AF:

0.000366

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Oct 11, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 07, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 17, 2024

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.8305C>T (p.Leu2769Phe) results in a non-conservative amino acid change located in the REJ domain (IPR014010) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 246822 control chromosomes, predominantly at a frequency of 0.0032 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKD1 causing Polycystic Kidney Disease 1 phenotype (0.0005). However, the gnomAD database has noted that pseudogenic regions are not flagged and a 90 bp region surrounding this variant was found to have >95% homology to 4 different loci on chr 16. Therefore population data must be interpreted with caution. c.8305C>T has been reported in the literature in at least 1 individual affected with Polycystic Kidney Disease (example, Kurashige_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Polycystic Kidney Disease 1. Co-occurrences with other pathogenic variant(s) have been reported (PKD2 c.2533C>T, p.Arg845*), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24611717). ClinVar contains an entry for this variant (Variation ID: 440092). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

PKD1-related disorder

Benign:1

Feb 13, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.044

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.8

M;M

PhyloP100

9.5

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.26

Sift

Uncertain

0.021

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.61

MutPred

0.30

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

MVP

0.78

ClinPred

0.20

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.23

gMVP

0.63

Mutation Taster

=4/96

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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