16-2079630-G-T

Variant names:

• chr16-2079630-G-T
• rs1053311636
• NM_000548.5:c.3358G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000548.5(TSC2):​c.3358G>T​(p.Val1120Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1120E) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 3.96
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2870436).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.3358G>T	p.Val1120Leu	missense	Exon 29 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.3355G>T	p.Val1119Leu	missense	Exon 29 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.3358G>T	p.Val1120Leu	missense	Exon 29 of 41	NP_001107854.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.3358G>T	p.Val1120Leu	missense	Exon 29 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.3358G>T	p.Val1120Leu	missense	Exon 29 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.3226G>T	p.Val1076Leu	missense	Exon 28 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74508

African (AFR) AF: 0.0000481 AC: 2 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000792 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	2	-	Tuberous sclerosis 2 (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	2.0	M
PhyloP100		4.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.46
Sift	Benign	0.10	T
Sift4G	Benign	0.71	T
Polyphen		0.93	P
Vest4		0.40
MutPred		0.18		Gain of helix (P = 0.0325)
MVP		0.87
ClinPred		0.41	T
GERP RS		4.7
Varity_R		0.063
gMVP		0.20
Mutation Taster		=84/16	polymorphism

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: rs1053311636; hg19: chr16-2129631;