rs145955373

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.11346C>T(p.Asp3782Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0039 in 1,612,888 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0039 ( 29 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.0510

Publications

6 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 links:

PKD1-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

PKD1-AS1 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 (BayesDel_noAF=-0.77).

BP6

Variant 16-2092112-G-A is Benign according to our data. Variant chr16-2092112-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.051 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00363 (553/152328) while in subpopulation SAS AF = 0.00621 (30/4830). AF 95% confidence interval is 0.00515. There are 2 homozygotes in GnomAd4. There are 247 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.11346C>T	p.Asp3782Asp	synonymous_variant	Exon 40 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.11346C>T	p.Asp3782Asp	synonymous_variant	Exon 40 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00363

AC:

553

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00621

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00562

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00455

AC:

1135

AN:

249620

AF XY:

0.00504

show subpopulations

Gnomad AFR exome

AF:

0.00124

Gnomad AMR exome

AF:

0.00298

Gnomad ASJ exome

AF:

0.00340

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00439

Gnomad NFE exome

AF:

0.00508

Gnomad OTH exome

AF:

0.00673

GnomAD4 exome

AF:

0.00393

AC:

5742

AN:

1460560

Hom.:

Cov.:

AF XY:

0.00422

AC XY:

3064

AN XY:

726584

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

33480

American (AMR)

AF:

0.00291

AC:

130

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00268

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00875

AC:

755

AN:

86258

European-Finnish (FIN)

AF:

0.00529

AC:

276

AN:

52152

Middle Eastern (MID)

AF:

0.0184

AC:

106

AN:

5768

European-Non Finnish (NFE)

AF:

0.00365

AC:

4060

AN:

1111974

Other (OTH)

AF:

0.00475

AC:

287

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

385

770

1154

1539

1924

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

142

284

426

568

710

<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:

0.00363

AC:

553

AN:

152328

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

247

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00151

AC:

AN:

41586

American (AMR)

AF:

0.00189

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00562

AC:

382

AN:

68020

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00354

Hom.:

Bravo

AF:

0.00319

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.00611

EpiControl

AF:

0.00628

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 07, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27401137, 19686598) -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PKD1: BP4, BP7 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 25, 2025

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease, adult type

Benign:3

May 30, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 09, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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.Asp3782Asp variant was identified as polymorphism in 6 of 550 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Rossetti 2012, Rossetti 2002). The variant was also identified in the following databases: in dbSNP (ID: rs145955373) as â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, ClinVar (1x, as benign by Prevention Genetics), ADPKD Mutation Database (as likely neutral). The variant was not identified in LOVD 3.0, or PKD1-LOVD databases. The variant was identified in control databases in 1274 of 276110 (5 homozygous) chromosomes at a frequency of 0.004614 in the following populations: African in 30 of 23896 chromosomes (freq. 0.0012), other in 40 of 6440 chromosomes (freq. 0.006), Latino in 106 of 34408 chromosomes (freq. 0.003), European in 669 of 125862 (2 homozygous) chromosomes (freq. 0.005), Ashkenazi Jewish in 36 of 10114 chromosomes (freq. 0.0035), East Asian in 1 of 18836 chromosomes (freq. 0.00005), Finnish in 118 of 25778 chromosomes (freq. 0.0045),and South Asian in 274 of 30776 (3 homozygous) chromosomes (freq. 0.009), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Asp3782Asp 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. A co-occurring pathogenic PKD1 variant (c.7864-1G>T, r.spl?) is identified in 1 individual with ADPKD in our laboratory, increasing the likelihood that p.Asp3782=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

-0.77

CADD

Benign

5.9

(source)

DANN

Benign

0.73

PhyloP100

-0.051

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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