16-2057112-G-T

Variant names:

• chr16-2057112-G-T
• rs45502703
• NM_000548.5:c.782G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PP3_Moderate BP6_Moderate

The NM_000548.5(TSC2):​c.782G>T​(p.Arg261Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R261G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.52
• Publications: 15 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• BP6: Variant 16-2057112-G-T is Benign according to our data. Variant chr16-2057112-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1465757.Status of the report is criteria_provided_single_submitter, 1 stars.

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.782G>T	p.Arg261Leu	missense	Exon 9 of 42	NP_000539.2
	TSC2	NM_001406689.1		c.-650G>T		5_prime_UTR_premature_start_codon_gain	Exon 9 of 42	NP_001393618.1
	TSC2	NM_001406690.1		c.-650G>T		5_prime_UTR_premature_start_codon_gain	Exon 9 of 42	NP_001393619.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.782G>T	p.Arg261Leu	missense	Exon 9 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.782G>T	p.Arg261Leu	missense	Exon 9 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.782G>T	p.Arg261Leu	missense	Exon 9 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000639 AC: 1 AN: 156508 AF XY: 0.0000121

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399130 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 690084

African (AFR) AF: 0.00 AC: 0 AN: 31594

American (AMR) AF: 0.0000280 AC: 1 AN: 35714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35740

South Asian (SAS) AF: 0.00 AC: 0 AN: 79240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078972

Other (OTH) AF: 0.00 AC: 0 AN: 57990

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 2 Benign:1

Dec 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.40		Gain of ubiquitination at K258 (P = 0.0577)
MVP		0.95
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.74
Mutation Taster		=14/86	disease causing

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: rs45502703; hg19: chr16-2107113;