rs36032671

chr16-2088669-TAA-Tchr16-2088669-TAA-TAchr16-2088669-TAA-TAAAchr16-2088669-TAA-TAAAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000548.5(TSC2):c.*61_*62del variant causes a 3 prime UTR 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 NM_000548.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3 O:2
• Conservation: PhyloP100: 4.51

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 50172.We mark this variant Likely_benign, oryginal submissions are: {not_provided=2, Uncertain_significance=1, Benign=1}. Variant chr16-2088669-TAA-T is described in Lovd as [Benign]. Variant chr16-2088669-TAA-T is described in Lovd as [Likely_benign].
• 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/exons	MANE	UniProt
TSC2	NM_000548.5	c.*61_*62del		3_prime_UTR_variant	42/42	ENST00000219476.9
PKD1	NM_001009944.3			downstream_gene_variant		ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.*61_*62del		3_prime_UTR_variant	42/42	5	NM_000548.5
PKD1	ENST00000262304.9			downstream_gene_variant		1	NM_001009944.3	P5

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

Gnomad4 AFR exome AF: 0.0145

Gnomad4 AMR exome AF: 0.0364

Gnomad4 ASJ exome AF: 0.0942

Gnomad4 EAS exome AF: 0.000219

Gnomad4 SAS exome AF: 0.0577

Gnomad4 FIN exome AF: 0.139

Gnomad4 NFE exome AF: 0.0961

Gnomad4 OTH exome AF: 0.0801

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

Gnomad4 AFR AF: 0.0171

Gnomad4 AMR AF: 0.0521

Gnomad4 ASJ AF: 0.0827

Gnomad4 EAS AF: 0.000585

Gnomad4 SAS AF: 0.0569

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.0918

Gnomad4 OTH AF: 0.0592

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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

- -

Tuberous sclerosis syndrome;C0751674:Lymphangiomyomatosis Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

-

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs36032671; hg19: chr16-2138670;