rs200509641

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001009944.3(PKD1):c.8111C>T(p.Ala2704Val) variant causes a missense change. The variant allele was found at a frequency of 0.000896 in 1,589,016 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. A2704T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 20)

Exomes 𝑓: 0.00092 ( 10 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.06

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008843273).

BP6

Variant 16-2104548-G-A is Benign according to our data. Variant chr16-2104548-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 440103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00066 (99/150012) while in subpopulation SAS AF = 0.00319 (15/4708). AF 95% confidence interval is 0.00196. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.8111C>T	p.Ala2704Val	missense_variant	Exon 22 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.8111C>T	p.Ala2704Val	missense_variant	Exon 22 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes

AF:

0.000660

AC:

AN:

149894

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000347

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000530

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000202

Gnomad SAS

AF:

0.00318

Gnomad FIN

AF:

0.00171

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000548

Gnomad OTH

AF:

0.000969

GnomAD2 exomes

AF:

0.00142

AC:

223

AN:

156602

AF XY:

0.00177

show subpopulations

Gnomad AFR exome

AF:

0.000121

Gnomad AMR exome

AF:

0.000274

Gnomad ASJ exome

AF:

0.000355

Gnomad EAS exome

AF:

0.000324

Gnomad FIN exome

AF:

0.000809

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.00204

GnomAD4 exome

AF:

0.000920

AC:

1324

AN:

1439004

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

806

AN XY:

714798

show subpopulations

African (AFR)

AF:

0.000423

AC:

AN:

33068

American (AMR)

AF:

0.000442

AC:

AN:

43012

Ashkenazi Jewish (ASJ)

AF:

0.000233

AC:

AN:

25718

East Asian (EAS)

AF:

0.000408

AC:

AN:

39192

South Asian (SAS)

AF:

0.00538

AC:

450

AN:

83660

European-Finnish (FIN)

AF:

0.00166

AC:

AN:

49452

Middle Eastern (MID)

AF:

0.00950

AC:

AN:

4106

European-Non Finnish (NFE)

AF:

0.000546

AC:

601

AN:

1101336

Other (OTH)

AF:

0.00163

AC:

AN:

59460

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

144

216

288

360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.000660

AC:

AN:

150012

Hom.:

Cov.:

AF XY:

0.000710

AC XY:

AN XY:

73196

show subpopulations

African (AFR)

AF:

0.000346

AC:

AN:

40474

American (AMR)

AF:

0.000529

AC:

AN:

15116

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.000202

AC:

AN:

4948

South Asian (SAS)

AF:

0.00319

AC:

AN:

4708

European-Finnish (FIN)

AF:

0.00171

AC:

AN:

10504

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000548

AC:

AN:

67520

Other (OTH)

AF:

0.000959

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.000849

Hom.:

Bravo

AF:

0.000635

ESP6500AA

AF:

0.000242

AC:

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.000895

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Jun 08, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PKD1: BP4, BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 02, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease, adult type

Benign:1

Nov 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely 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:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PKD1 p.Ala2704Val variant was identified in 1 of 74 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Bataille 2011). The variant was also identified in dbSNP (ID: rs200509641), LOVD 3.0 (2X), and the ADPKD Mutation Database (likely neutral). The variant was not identified in ClinVar, COGR, or PKD1-LOVD databases. The variant was identified in control databases in 239 of 180276 chromosomes at a frequency of 0.001 in the following populations: South Asian in 125 of 23404 chromosomes (freq. 0.005), European in 70 of 73288 chromosomes (freq. 0.001), Finnish in 19 of 15662 chromosomes (freq. 0.001), Other in 8 of 4820 chromosomes (freq. 0.002), Latino in 7 of 25668 chromosomes (freq. 0.0003), East Asian in 4 of 13122 chromosomes (freq.0.0003), African in 3 of 15856 chromosomes (freq. 0.0002), Ashkenazi Jewish in 3 of 8466 chromosomes (freq. 0.0003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. This variant was also identified in one individual from our laboratory with a co-occurring pathogenic variant in PKD2 (c.1704dupT, p.Val569CysfsX4), increasing the likelihood this variant does not have clinical significance. The p.Ala2704 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Autosomal dominant polycystic kidney disease

Benign:1

Jan 01, 2019

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.80

T;T

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.0088

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;L

PhyloP100

4.1

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.12

Sift

Benign

0.081

T;T

Sift4G

Benign

0.088

T;T

Polyphen

0.60

P;P

Vest4

0.056

MVP

0.49

ClinPred

0.020

GERP RS

-0.39

Varity_R

0.027

gMVP

0.15

Mutation Taster

=77/23

polymorphism

(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