16-2050409-A-T

Variant names:

• chr16-2050409-A-T
• rs140618379
• NM_000548.5:c.148A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001406680.1(TSC2):​c.-669A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,658 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSC2 NM_001406680.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.744
• 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07648942).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406680.1. 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.148A>T	p.Met50Leu	missense	Exon 3 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406680.1		c.-669A>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 42	NP_001393609.1
	TSC2	NM_001406681.1		c.-298A>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 40	NP_001393610.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.148A>T	p.Met50Leu	missense	Exon 3 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.148A>T	p.Met50Leu	missense	Exon 3 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.148A>T	p.Met50Leu	missense	Exon 3 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461658 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727122

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111906

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.64
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.74
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.14
Sift	Benign	0.43	T
Sift4G	Benign	0.88	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.54		Loss of catalytic residue at M50 (P = 5e-04)
MVP		0.28
ClinPred		0.025	T
GERP RS		2.6
Varity_R		0.032
gMVP		0.097
Mutation Taster		=15/185	disease causing

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: rs140618379; hg19: chr16-2100410;