rs76184385

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001009944.3(PKD1):c.8964G>A(p.Ala2988Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00776 in 1,611,016 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0079 ( 65 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.761

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.016).

BP6

Variant 16-2102618-C-T is Benign according to our data. Variant chr16-2102618-C-T is described in ClinVar as Benign. ClinVar VariationId is 257036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.761 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00637 (970/152370) while in subpopulation EAS AF = 0.00926 (48/5186). AF 95% confidence interval is 0.00717. There are 8 homozygotes in GnomAd4. There are 534 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.8964G>A	p.Ala2988Ala	synonymous_variant	Exon 25 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.8964G>A	p.Ala2988Ala	synonymous_variant	Exon 25 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes

AF:

0.00638

AC:

971

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00569

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00923

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.0206

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00769

Gnomad OTH

AF:

0.00622

GnomAD2 exomes

AF:

0.00748

AC:

1848

AN:

247014

AF XY:

0.00738

show subpopulations

Gnomad AFR exome

AF:

0.000521

Gnomad AMR exome

AF:

0.00892

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00985

Gnomad FIN exome

AF:

0.0183

Gnomad NFE exome

AF:

0.00660

Gnomad OTH exome

AF:

0.00798

GnomAD4 exome

AF:

0.00791

AC:

11537

AN:

1458646

Hom.:

Cov.:

AF XY:

0.00780

AC XY:

5660

AN XY:

725648

show subpopulations

African (AFR)

AF:

0.00138

AC:

AN:

33418

American (AMR)

AF:

0.00803

AC:

359

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

26122

East Asian (EAS)

AF:

0.0145

AC:

574

AN:

39696

South Asian (SAS)

AF:

0.00549

AC:

473

AN:

86164

European-Finnish (FIN)

AF:

0.0186

AC:

970

AN:

52072

Middle Eastern (MID)

AF:

0.00244

AC:

AN:

4506

European-Non Finnish (NFE)

AF:

0.00774

AC:

8610

AN:

1111754

Other (OTH)

AF:

0.00809

AC:

487

AN:

60202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

718

1437

2155

2874

3592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

332

664

996

1328

1660

<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:

0.00637

AC:

970

AN:

152370

Hom.:

Cov.:

AF XY:

0.00717

AC XY:

534

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

41598

American (AMR)

AF:

0.00568

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00926

AC:

AN:

5186

South Asian (SAS)

AF:

0.00580

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0206

AC:

219

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00769

AC:

523

AN:

68028

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

146

194

243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00607

Hom.:

Bravo

AF:

0.00515

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.00692

EpiControl

AF:

0.00670

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Aug 20, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PKD1: BP4, BP7, BS1, 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

- -

Jan 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 10854095, 11558899, 12007219, 22383692, 22608885, 24374109) -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease, adult type

Benign:1

Jul 25, 2019

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.Ala2988Ala variant was identified in 9 of 1202 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD (Perrichot 2000, Inoue 2002, Mizoguchi 2001, Rossetti 2012, Tan 2012, Tan 2014). The variant was also identified in dbSNP (ID: rs76184385) and ADPKD Mutation Database (as likely neutral). This variant was identified in the 1000 Genomes Project in 31 of 5000 chromosomes (frequency: 0.006), NHLBI GO Exome Sequencing Project in 54 of 8570 European American (freq. 0.006) and in 4 of 4374 of African American alleles (freq. 0.0009).The p.Ala2988Ala variant was also identified in Exome Aggregation Consortium database (March 14, 2016) in 837 (6 homozygous) of 118036 chromosomes (freq. 0.007) in the following populations: European in 412 of 64634 chromosomes (freq. 0.006), Finnish in 120 of 6556 chromosomes (freq. 0.02), Latino in 105 of 11458 chromosomes (freq. 0.009), East Asian in 100 of 8594 chromosomes (freq. 0.01), South Asian in 87 of 16494 chromosomes (freq. 0.005), African in 7 of 9428 chromosomes (freq. 0.0007) and Other in 6 of 872 chromosomes (freq. 0.007), increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Ala2988Ala variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site.The variant occurs outside of the splicing consensus sequence and 1 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. Two population studies by Perrichot (2000) and Mizoguchi (2001) classified the variant as polymorphism since the variant does not lead to the modification of the encoded amino acid. In addition, another population study by Rossetti (2012) classified the variant as known exonic polymorphic variant. In addition, the variant was identified with a co-occurring pathogenic PKD1 variant in our lab (p.Ala3571_Val3572del), increasing the likelihood that the p.Ala2988Ala variant does not have clinical significance. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

2.9

(source)

DANN

Benign

0.43

PhyloP100

-0.76

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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