rs137854365

Positions:

• chr16-2088661-GAAAT-G
• chr16-2088661-G-GAAAT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000548.5(TSC2):​c.*59_*62del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,562,330 control chromosomes in the GnomAD database, including 42 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (20 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (22 hom.)
• Consequence: TSC2 NM_000548.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:2
• Conservation: PhyloP100: -0.631

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 -16 ACMG points.

• BP6: Variant 16-2088661-GAAAT-G is Benign according to our data. Variant chr16-2088661-GAAAT-G is described in ClinVar as [Likely_benign]. Clinvar id is 49664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088661-GAAAT-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00988 (1493/151052) while in subpopulation AFR AF= 0.0323 (1340/41478). AF 95% confidence interval is 0.0309. There are 20 homozygotes in gnomad4. There are 696 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1493 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.*59_*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.*59_*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: 0.00989 AC: 1492 AN: 150934 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00388

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.00690

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000550

Gnomad OTH AF: 0.00583

GnomAD3 exomes AF: 0.00381 AC: 666 AN: 174634 Hom.: 6 AF XY: 0.00357 AC XY: 340 AN XY: 95228

Gnomad AFR exome AF: 0.0313

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.00207

Gnomad SAS exome AF: 0.00674

Gnomad FIN exome AF: 0.000132

Gnomad NFE exome AF: 0.000570

Gnomad OTH exome AF: 0.00354

GnomAD4 exome AF: 0.00187 AC: 2633 AN: 1411278 Hom.: 22 AF XY: 0.00192 AC XY: 1344 AN XY: 699972

Gnomad4 AFR exome AF: 0.0350

Gnomad4 AMR exome AF: 0.00238

Gnomad4 ASJ exome AF: 0.0000391

Gnomad4 EAS exome AF: 0.00123

Gnomad4 SAS exome AF: 0.00692

Gnomad4 FIN exome AF: 0.000138

Gnomad4 NFE exome AF: 0.000507

Gnomad4 OTH exome AF: 0.00363

GnomAD4 genome AF: 0.00988 AC: 1493 AN: 151052 Hom.: 20 Cov.: 33 AF XY: 0.00943 AC XY: 696 AN XY: 73790

Gnomad4 AFR AF: 0.0323

Gnomad4 AMR AF: 0.00388

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00213

Gnomad4 SAS AF: 0.00691

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000550

Gnomad4 OTH AF: 0.00577

Alfa AF: 0.000994 Hom.: 0

Bravo AF: 0.0114

Asia WGS AF: 0.00841 AC: 31 AN: 3464

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis syndrome Benign:1 Other:2

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

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2018

- -

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: rs137854184; hg19: chr16-2138662;