chr16-2111654-G-C

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.3513C>G(p.Thr1171Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00656 in 1,573,854 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0065 ( 67 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.05

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 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=-0.9).

BP6

Variant 16-2111654-G-C is Benign according to our data. Variant chr16-2111654-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.05 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00684 (1041/152288) while in subpopulation NFE AF = 0.00756 (514/68004). AF 95% confidence interval is 0.00702. There are 7 homozygotes in GnomAd4. There are 583 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.3513C>G	p.Thr1171Thr	synonymous_variant	Exon 15 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.3513C>G	p.Thr1171Thr	synonymous_variant	Exon 15 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00684

AC:

1041

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.0378

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00756

Gnomad OTH

AF:

0.00527

GnomAD2 exomes

AF:

0.00705

AC:

1274

AN:

180654

AF XY:

0.00655

show subpopulations

Gnomad AFR exome

AF:

0.000591

Gnomad AMR exome

AF:

0.00209

Gnomad ASJ exome

AF:

0.00824

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0350

Gnomad NFE exome

AF:

0.00702

Gnomad OTH exome

AF:

0.00559

GnomAD4 exome

AF:

0.00653

AC:

9289

AN:

1421566

Hom.:

Cov.:

AF XY:

0.00636

AC XY:

4477

AN XY:

703808

show subpopulations

African (AFR)

AF:

0.000735

AC:

AN:

32648

American (AMR)

AF:

0.00219

AC:

AN:

38852

Ashkenazi Jewish (ASJ)

AF:

0.00854

AC:

217

AN:

25422

East Asian (EAS)

AF:

0.00

AC:

AN:

37736

South Asian (SAS)

AF:

0.000697

AC:

AN:

81802

European-Finnish (FIN)

AF:

0.0353

AC:

1739

AN:

49222

Middle Eastern (MID)

AF:

0.00244

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

0.00625

AC:

6833

AN:

1093086

Other (OTH)

AF:

0.00552

AC:

324

AN:

58704

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

646

1292

1938

2584

3230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

236

472

708

944

1180

<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:

0.00684

AC:

1041

AN:

152288

Hom.:

Cov.:

AF XY:

0.00783

AC XY:

583

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41564

American (AMR)

AF:

0.00216

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0378

AC:

401

AN:

10618

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00756

AC:

514

AN:

68004

Other (OTH)

AF:

0.00521

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

100

151

201

251

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:

0.00743

Hom.:

Bravo

AF:

0.00400

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

Feb 18, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22383692, 17574468, 18837007) -

Mar 01, 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, BP7, BS2 -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 27, 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:1

Mar 26, 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.Thr1171Thr variant was identified in 1 of 50 proband chromosomes (frequency: 0.020) from individuals or families with ADPKD (Tan 2014); however, control chromosomes were not evaluated in this study, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs143784787) as â€šÃ„ÃºWith Benign Alleleâ€šÃ„Ã¹; in Clinvitae and ClinVar as benign by Prevention Genetics; in the ADPKD Mutation Database 5x as likely neutral; and in PKD1-LOVD 3.0 with unknown effect. The variant was not identified in the GeneInsight COGR, MutDB, and PKD1-LOVD databases. This variant was further identified in the 1000 Genomes Project in 13 of 5000 chromosomes (frequency: 0.0026); HAPMAP-EUR in 11 of 1006 chromosomes (frequency: 0.011) and HAPMAP-AMR in 2 of 694 chromosomes (frequency: 0.003); and the NHLBI GO Exome Sequencing Project in 5 of 4248 European American (frequency: 0.001) and 46 of 8432 African American (frequency: 0.005) alleles. In addition, the variant was identified in the Exome Aggregation Consortium database (August 8th 2016) in 199 of 28266 chromosomes (frequency: 0.007) in the following populations: European (Finnish) in 16 of 304 chromosomes (freq. 0.052), European (Non-Finnish) in 165 of 13016 chromosomes (freq. 0.012), Latino in 4of 1266 chromosomes (frequency: 0.003), African in 4 of 2842 chromosomes (freq. 0.001), South Asian in 6 of 8894 chromosomes (freq. 0.0006), and in other in 4 of 250 chromosomes (freq. 0.016) but was not seen in the East Asian populations increasing the likelihood this could be a low frequency benign variant. The p.Thr1171Thr 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. In addition in this case a pathogenic PKD1 truncating variant (p.Ser1488LeufsX46) was identified adding to the evidence that the c.3513C>G variant does not have clinical significance. In addition the variant was identified in our lab in a patient with PKD as co-occurring with a pathogenic PKD1 truncating variant (p.Ser1488LeufsX46) adding to the evidence that the c.3513C>G 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

-0.90

CADD

Benign

0.13

(source)

DANN

Benign

0.62

PhyloP100

-1.1

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)

0.070

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