rs752498350

Variant names:

• chr16-2053413-C-G
• rs752498350
• NM_000548.5:c.297C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-2053413-C-G
• chr16-2053413-C-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.297C>G​(p.His99Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H99H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.63
• Publications: 2 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=0.28542024).

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.297C>G	p.His99Gln	missense	Exon 4 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.297C>G	p.His99Gln	missense	Exon 4 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.297C>G	p.His99Gln	missense	Exon 4 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.297C>G	p.His99Gln	missense	Exon 4 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.297C>G	p.His99Gln	missense	Exon 4 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.297C>G	p.His99Gln	missense	Exon 4 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 201818 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1434298 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 710938

African (AFR) AF: 0.00 AC: 0 AN: 32944

American (AMR) AF: 0.00 AC: 0 AN: 40818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25574

East Asian (EAS) AF: 0.00 AC: 0 AN: 38306

South Asian (SAS) AF: 0.00 AC: 0 AN: 82026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5478

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099410

Other (OTH) AF: 0.00 AC: 0 AN: 59290

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Aug 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H99Q variant (also known as c.297C>G), located in coding exon 3 of the TSC2 gene, results from a C to G substitution at nucleotide position 297. The histidine at codon 99 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	1.9
DANN	Benign	0.94
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.3	L
PhyloP100		-2.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.38
Sift	Benign	0.19	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.59
MutPred		0.43		Loss of loop (P = 0.0374)
MVP		0.76
ClinPred		0.96	D
GERP RS		-4.6
PromoterAI		0.12	Neutral
Varity_R		0.24
gMVP		0.60
Mutation Taster		=39/61	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: rs752498350; hg19: chr16-2103414;