16-2088868-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001009944.3(PKD1):c.*859G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 521,830 control chromosomes in the GnomAD database, including 7,701 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 4787 hom., cov: 32)

Exomes 𝑓: 0.099 ( 2914 hom. )

Consequence

PKD1
NM_001009944.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0960

Publications

9 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:

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC2 Gene-Disease associations (from GenCC):

tuberous sclerosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
tuberous sclerosis 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
lymphangioleiomyomatosis
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
tuberous sclerosis complex
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TSC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 16-2088868-C-T is Benign according to our data. Variant chr16-2088868-C-T is described in ClinVar as [Benign]. Clinvar id is 1245044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.*859G>A		3_prime_UTR_variant	Exon 46 of 46	ENST00000262304.9	NP_001009944.3
TSC2	NM_000548.5 link	c.*258C>T		3_prime_UTR_variant	Exon 42 of 42	ENST00000219476.9	NP_000539.2	P49815-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 link	c.*859G>A		3_prime_UTR_variant	Exon 46 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1
TSC2	ENST00000219476.9 link	c.*258C>T		3_prime_UTR_variant	Exon 42 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.207

AC:

29754

AN:

143528

Hom.:

4776

Cov.:

show subpopulations

Gnomad AFR

AF:

0.469

Gnomad AMI

AF:

0.120

Gnomad AMR

AF:

0.152

Gnomad ASJ

AF:

0.158

Gnomad EAS

AF:

0.000801

Gnomad SAS

AF:

0.0337

Gnomad FIN

AF:

0.129

Gnomad MID

AF:

0.217

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.190

GnomAD4 exome

AF:

0.0991

AC:

37461

AN:

378198

Hom.:

2914

Cov.:

AF XY:

0.0939

AC XY:

18658

AN XY:

198660

show subpopulations

African (AFR)

AF:

0.435

AC:

4627

AN:

10642

American (AMR)

AF:

0.109

AC:

1665

AN:

15330

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

1697

AN:

11822

East Asian (EAS)

AF:

0.0000382

AC:

AN:

26186

South Asian (SAS)

AF:

0.0346

AC:

1519

AN:

43878

European-Finnish (FIN)

AF:

0.107

AC:

2407

AN:

22394

Middle Eastern (MID)

AF:

0.181

AC:

295

AN:

1628

European-Non Finnish (NFE)

AF:

0.101

AC:

22570

AN:

224536

Other (OTH)

AF:

0.123

AC:

2680

AN:

21782

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1434

2867

4301

5734

7168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.207

AC:

29800

AN:

143632

Hom.:

4787

Cov.:

AF XY:

0.203

AC XY:

14251

AN XY:

70124

show subpopulations

African (AFR)

AF:

0.469

AC:

18089

AN:

38560

American (AMR)

AF:

0.152

AC:

2157

AN:

14210

Ashkenazi Jewish (ASJ)

AF:

0.158

AC:

525

AN:

3324

East Asian (EAS)

AF:

0.000803

AC:

AN:

4982

South Asian (SAS)

AF:

0.0335

AC:

155

AN:

4622

European-Finnish (FIN)

AF:

0.129

AC:

1281

AN:

9900

Middle Eastern (MID)

AF:

0.230

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.109

AC:

7044

AN:

64874

Other (OTH)

AF:

0.188

AC:

372

AN:

1978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

938

1876

2815

3753

4691

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.134

Hom.:

3168

Bravo

AF:

0.214

Asia WGS

AF:

0.0420

AC:

147

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.6

(source)

DANN

Benign

0.56

PhyloP100

0.096

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Mutation Taster

=99/1

polymorphism (auto)

(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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16-2088868-C-T

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