16-2055054-A-G

Variant names:

• chr16-2055054-A-G
• rs2073636
• NM_000548.5:c.482-348A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000548.5(TSC2):​c.482-348A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 403,308 control chromosomes in the GnomAD database, including 87,932 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.68 (36202 hom., cov: 31)
  • Exomes 𝑓: 0.64 (51730 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.236
• Publications: 24 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]

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.482-348A>G		intron_variant	Intron 5 of 41	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.482-348A>G		intron_variant	Intron 5 of 41	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.683 AC: 103695 AN: 151842 Hom.: 36139 Cov.: 31

Gnomad AFR AF: 0.829

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.650

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.795

Gnomad SAS AF: 0.706

Gnomad FIN AF: 0.580

Gnomad MID AF: 0.659

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.665

GnomAD4 exome AF: 0.638 AC: 160320 AN: 251348 Hom.: 51730 Cov.: 0 AF XY: 0.644 AC XY: 86370 AN XY: 134204

African (AFR) AF: 0.822 AC: 5943 AN: 7232

American (AMR) AF: 0.662 AC: 8134 AN: 12290

Ashkenazi Jewish (ASJ) AF: 0.594 AC: 4156 AN: 6996

East Asian (EAS) AF: 0.778 AC: 10155 AN: 13054

South Asian (SAS) AF: 0.701 AC: 29256 AN: 41708

European-Finnish (FIN) AF: 0.599 AC: 7021 AN: 11722

Middle Eastern (MID) AF: 0.659 AC: 635 AN: 964

European-Non Finnish (NFE) AF: 0.601 AC: 86498 AN: 143928

Other (OTH) AF: 0.633 AC: 8522 AN: 13454

GnomAD4 genome AF: 0.683 AC: 103814 AN: 151960 Hom.: 36202 Cov.: 31 AF XY: 0.680 AC XY: 50531 AN XY: 74266

African (AFR) AF: 0.829 AC: 34389 AN: 41488

American (AMR) AF: 0.650 AC: 9926 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 2105 AN: 3472

East Asian (EAS) AF: 0.795 AC: 4090 AN: 5146

South Asian (SAS) AF: 0.706 AC: 3402 AN: 4818

European-Finnish (FIN) AF: 0.580 AC: 6101 AN: 10528

Middle Eastern (MID) AF: 0.678 AC: 198 AN: 292

European-Non Finnish (NFE) AF: 0.612 AC: 41555 AN: 67930

Other (OTH) AF: 0.669 AC: 1412 AN: 2112

Alfa AF: 0.623 Hom.: 53598

Bravo AF: 0.693

Asia WGS AF: 0.775 AC: 2692 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.64
DANN	Benign	0.28
PhyloP100		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	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: rs2073636; hg19: chr16-2105055;