chr16-2053394-G-T

Variant names:

• chr16-2053394-G-T
• rs1222477746
• NM_000548.5:c.278G>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.278G>T​(p.Arg93Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000695 in 1,439,354 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R93Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.02
• 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=0.35524228).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.278G>T	p.Arg93Leu	missense	Exon 4 of 42	NP_000539.2
	TSC2	NM_001406680.1		c.-539G>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 42	NP_001393609.1
	TSC2	NM_001406681.1		c.-168G>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 40	NP_001393610.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.278G>T	p.Arg93Leu	missense	Exon 4 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.278G>T	p.Arg93Leu	missense	Exon 4 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.278G>T	p.Arg93Leu	missense	Exon 4 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439354 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 713830

African (AFR) AF: 0.00 AC: 0 AN: 33116

American (AMR) AF: 0.00 AC: 0 AN: 41690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25656

East Asian (EAS) AF: 0.00 AC: 0 AN: 38608

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50788

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5392

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102152

Other (OTH) AF: 0.00 AC: 0 AN: 59450

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.0
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.25
Sift	Benign	0.68	T
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.59
MutPred		0.40		Loss of disorder (P = 0.0475)
MVP		0.69
ClinPred		0.90	D
GERP RS		4.8
PromoterAI		0.0054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.35
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1222477746; hg19: chr16-2103395; COSMIC: COSV54766545; COSMIC: COSV54766545;