16-2103870-C-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.8187G>A(p.Ser2729Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,588,834 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0051 ( 16 hom., cov: 28)

Exomes 𝑓: 0.00071 ( 6 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -5.68

Publications

1 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=-0.75).

BP6

Variant 16-2103870-C-T is Benign according to our data. Variant chr16-2103870-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.68 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00514 (730/142118) while in subpopulation AFR AF = 0.0177 (667/37728). AF 95% confidence interval is 0.0166. There are 16 homozygotes in GnomAd4. There are 332 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.8187G>A	p.Ser2729Ser	synonymous_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.8187G>A	p.Ser2729Ser	synonymous_variant	Exon 23 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00511

AC:

725

AN:

141994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00147

Gnomad EAS

AF:

0.00156

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00662

Gnomad NFE

AF:

0.000168

Gnomad OTH

AF:

0.00567

GnomAD2 exomes

AF:

0.00174

AC:

415

AN:

239026

AF XY:

0.00138

show subpopulations

Gnomad AFR exome

AF:

0.0203

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00234

Gnomad EAS exome

AF:

0.00199

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000131

Gnomad OTH exome

AF:

0.000851

GnomAD4 exome

AF:

0.000705

AC:

1020

AN:

1446716

Hom.:

Cov.:

AF XY:

0.000599

AC XY:

431

AN XY:

719428

show subpopulations

African (AFR)

AF:

0.0205

AC:

678

AN:

33030

American (AMR)

AF:

0.00118

AC:

AN:

43906

Ashkenazi Jewish (ASJ)

AF:

0.00148

AC:

AN:

25750

East Asian (EAS)

AF:

0.000897

AC:

AN:

39000

South Asian (SAS)

AF:

0.000163

AC:

AN:

85708

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50860

Middle Eastern (MID)

AF:

0.00197

AC:

AN:

4066

European-Non Finnish (NFE)

AF:

0.000101

AC:

112

AN:

1104976

Other (OTH)

AF:

0.00140

AC:

AN:

59420

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

104

157

209

261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00514

AC:

730

AN:

142118

Hom.:

Cov.:

AF XY:

0.00483

AC XY:

332

AN XY:

68788

show subpopulations

African (AFR)

AF:

0.0177

AC:

667

AN:

37728

American (AMR)

AF:

0.00190

AC:

AN:

14216

Ashkenazi Jewish (ASJ)

AF:

0.00147

AC:

AN:

3402

East Asian (EAS)

AF:

0.00157

AC:

AN:

4468

South Asian (SAS)

AF:

0.00

AC:

AN:

4086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9538

Middle Eastern (MID)

AF:

0.00709

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000168

AC:

AN:

65582

Other (OTH)

AF:

0.00561

AC:

AN:

1962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

120

150

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:

0.00294

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 20, 2019

Athena Diagnostics

Significance: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

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.Ser2729Ser variant was identified in 2 of 164 proband chromosomes (frequency: 0.012) from individuals or families with ADPKD (Garcia-Gonzalez 2007). This variant was identified in the 1000 Genomes Project in 41 of 5000 chromosomes (frequency: 0.0082), NHLBI GO Exome Sequencing Project in 2 of 8532 European American alleles (frequency: 0.000234412), and 45 of 4324 African American alleles (frequency: 0.010407031), Exome Aggregation Consortium database (August 8, 2016) in 218 (4 homozygous) of 83288 chromosomes (frequency: 0.002617) in the following populations: African in 177 of 6580 chromosomes (frequency: 0.0269), Latino in 11 of 7048 chromosomes (frequency: 0.001561), European (Non-Finnish) in 15 of 45562 chromosomes (frequency: 0.0003292), South Asian in 1 of 13388 chromosomes (frequency: 0.00007469), East Asian in 14 of 5720 (frequency: 0.002448) but was not seen in European (Finnish) and Other populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. 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 variant was also identified in dbSNP (ID: rs28674911) as â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, ClinVar and Clinvitae (benign, by Prevention Genetics), ADPKD Mutation Database (Likely neutral). The p.Ser2729Ser 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, and HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Autosomal dominant polycystic kidney disease

Benign:1

Jan 01, 2019

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:1

Apr 01, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17574468) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.86

(source)

DANN

Benign

0.53

PhyloP100

-5.7

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

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