NM_001009944.3:c.8109C>T

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.8109C>T(p.Thr2703Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,591,226 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 4 hom., cov: 20)

Exomes 𝑓: 0.00095 ( 9 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.87

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 16-2104550-G-A is Benign according to our data. Variant chr16-2104550-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.87 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00375 (563/150032) while in subpopulation AFR AF = 0.0105 (425/40436). AF 95% confidence interval is 0.00969. There are 4 homozygotes in GnomAd4. There are 285 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.8109C>T	p.Thr2703Thr	synonymous_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.8109C>T	p.Thr2703Thr	synonymous_variant	Exon 22 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes

AF:

0.00376

AC:

564

AN:

149914

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00139

Gnomad ASJ

AF:

0.000868

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000424

Gnomad FIN

AF:

0.00599

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000607

Gnomad OTH

AF:

0.00387

GnomAD2 exomes

AF:

0.00135

AC:

213

AN:

157772

AF XY:

0.00124

show subpopulations

Gnomad AFR exome

AF:

0.0108

Gnomad AMR exome

AF:

0.000428

Gnomad ASJ exome

AF:

0.000946

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00480

Gnomad NFE exome

AF:

0.000608

Gnomad OTH exome

AF:

0.000903

GnomAD4 exome

AF:

0.000949

AC:

1368

AN:

1441194

Hom.:

Cov.:

AF XY:

0.000938

AC XY:

672

AN XY:

716124

show subpopulations

African (AFR)

AF:

0.0130

AC:

429

AN:

33100

American (AMR)

AF:

0.000508

AC:

AN:

43268

Ashkenazi Jewish (ASJ)

AF:

0.00101

AC:

AN:

25764

East Asian (EAS)

AF:

0.000204

AC:

AN:

39240

South Asian (SAS)

AF:

0.000262

AC:

AN:

83928

European-Finnish (FIN)

AF:

0.00466

AC:

231

AN:

49620

Middle Eastern (MID)

AF:

0.00341

AC:

AN:

4110

European-Non Finnish (NFE)

AF:

0.000480

AC:

529

AN:

1102588

Other (OTH)

AF:

0.00146

AC:

AN:

59576

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

124

186

248

310

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:

0.00375

AC:

563

AN:

150032

Hom.:

Cov.:

AF XY:

0.00389

AC XY:

285

AN XY:

73232

show subpopulations

African (AFR)

AF:

0.0105

AC:

425

AN:

40436

American (AMR)

AF:

0.00139

AC:

AN:

15124

Ashkenazi Jewish (ASJ)

AF:

0.000868

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

4952

South Asian (SAS)

AF:

0.000425

AC:

AN:

4708

European-Finnish (FIN)

AF:

0.00599

AC:

AN:

10518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000607

AC:

AN:

67546

Other (OTH)

AF:

0.00383

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

100

125

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:

0.000612

Hom.:

Bravo

AF:

0.00398

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 05, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 25, 2025

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease, adult type

Benign:1

Oct 01, 2018

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:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PKD1 p.Thr2703= variant was not identified in the literature nor was it identified in the LOVD 3.0 or PKD1-LOVD databases. The variant was identified in dbSNP (ID: rs149879790) as "With Likely benign allele", ClinVar (classified as likely benign by PreventionGenetics), and ADPKD Mutation Database (as likely neutral by Athena Diagnostics). The variant was identified in control databases in 330 of 181400 chromosomes at a frequency of 0.002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 180 of 15966 chromosomes (freq: 0.01), Other in 3 of 4834 chromosomes (freq: 0.0006), Latino in 12 of 25804 chromosomes (freq: 0.0005), European in 41 of 73996 chromosomes (freq: 0.0006), Ashkenazi Jewish in 6 of 8472 chromosomes (freq: 0.0007), Finnish in 86 of 15602 chromosomes (freq: 0.006), and South Asian in 2 of 23480 chromosomes (freq: 0.00009); it was not observed in the East Asian population. The p.Thr2703= variant is not expected to have clinical significance because it does not result in a change of amino acid and occurs at a non-highly conserved nucleotide at a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.92

(source)

DANN

Benign

0.77

PhyloP100

-1.9

Mutation Taster

=100/0

polymorphism

(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