rs36032671

Variant names:

• chr16-2088669-TAA-T
• rs36032671
• ENST00000439117.6:n.*4652_*4653delAA

Your query was ambiguous. Multiple possible variants found:

• chr16-2088669-TAA-T
• chr16-2088669-TAA-TA
• chr16-2088669-TAA-TAAA
• chr16-2088669-TAA-TAAAA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The ENST00000439117.6(TSC2):​n.*4652_*4653delAA variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.0859 in 1,547,878 control chromosomes in the GnomAD database, including 6,372 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.065 (439 hom., cov: 32)
  • Exomes 𝑓: 0.088 (5933 hom.)
• Consequence: TSC2 ENST00000439117.6 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3 O:2
• Conservation: PhyloP100: 4.51
• Publications: 3 publications found

Genes affected

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]

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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 16-2088669-TAA-T is Benign according to our data. Variant chr16-2088669-TAA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 50172.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.*61_*62delAA		3_prime_UTR_variant	Exon 42 of 42	ENST00000219476.9	NP_000539.2
PKD1	NM_001009944.3	c.*1056_*1057delTT		downstream_gene_variant		ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.*61_*62delAA		3_prime_UTR_variant	Exon 42 of 42	5	NM_000548.5	ENSP00000219476.3
PKD1	ENST00000262304.9	c.*1056_*1057delTT		downstream_gene_variant		1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.0654 AC: 9902 AN: 151502 Hom.: 439 Cov.: 32

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0521

Gnomad ASJ AF: 0.0827

Gnomad EAS AF: 0.000583

Gnomad SAS AF: 0.0571

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0918

Gnomad OTH AF: 0.0598

GnomAD4 exome AF: 0.0882 AC: 123139 AN: 1396260 Hom.: 5933 AF XY: 0.0874 AC XY: 60431 AN XY: 691458

African (AFR) AF: 0.0145 AC: 448 AN: 30824

American (AMR) AF: 0.0364 AC: 1366 AN: 37490

Ashkenazi Jewish (ASJ) AF: 0.0942 AC: 2391 AN: 25394

East Asian (EAS) AF: 0.000219 AC: 8 AN: 36608

South Asian (SAS) AF: 0.0577 AC: 4695 AN: 81380

European-Finnish (FIN) AF: 0.139 AC: 4916 AN: 35368

Middle Eastern (MID) AF: 0.0545 AC: 310 AN: 5692

European-Non Finnish (NFE) AF: 0.0961 AC: 104342 AN: 1085266

Other (OTH) AF: 0.0801 AC: 4663 AN: 58238

GnomAD4 genome AF: 0.0653 AC: 9899 AN: 151618 Hom.: 439 Cov.: 32 AF XY: 0.0666 AC XY: 4938 AN XY: 74128

African (AFR) AF: 0.0171 AC: 705 AN: 41138

American (AMR) AF: 0.0521 AC: 795 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0827 AC: 287 AN: 3472

East Asian (EAS) AF: 0.000585 AC: 3 AN: 5130

South Asian (SAS) AF: 0.0569 AC: 274 AN: 4814

European-Finnish (FIN) AF: 0.136 AC: 1437 AN: 10544

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0918 AC: 6237 AN: 67958

Other (OTH) AF: 0.0592 AC: 124 AN: 2096

Alfa AF: 0.0230 Hom.: 18

Bravo AF: 0.0559

Asia WGS AF: 0.0300 AC: 104 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1 Other:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

not specified Benign:2

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome;C0751674:Lymphangiomyomatosis Other:1

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs36032671; hg19: chr16-2138670; COSMIC: COSV104573743; COSMIC: COSV104573743;