16-2061882-C-G

Variant names:

• chr16-2061882-C-G
• rs201525586
• NM_000548.5:c.1131C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP6

The NM_000548.5(TSC2):​c.1131C>G​(p.Ser377Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,182 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S377G) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.767
• Publications: 7 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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 28 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 16-2061882-C-G is Benign according to our data. Variant chr16-2061882-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1002448.

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.1131C>G	p.Ser377Arg	missense	Exon 12 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.1131C>G	p.Ser377Arg	missense	Exon 12 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.1131C>G	p.Ser377Arg	missense	Exon 12 of 41	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.1131C>G	p.Ser377Arg	missense	Exon 12 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.1131C>G	p.Ser377Arg	missense	Exon 12 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.1131C>G	p.Ser377Arg	missense	Exon 12 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1

Oct 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 377 of the TSC2 protein (p.Ser377Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1002448). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S377R variant (also known as c.1131C>G), located in coding exon 11 of the TSC2 gene, results from a C to G substitution at nucleotide position 1131. The serine at codon 377 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

not provided Benign:1

Jul 05, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18466115)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.77
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.40
Sift	Benign	0.032	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.33		Gain of catalytic residue at S377 (P = 0.0464)
MVP		0.84
ClinPred		0.75	D
GERP RS		4.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.38
gMVP		0.59
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs201525586; hg19: chr16-2111883;