rs45458694

Variant names:

• chr16-2060811-C-A
• rs45458694
• NM_000548.5:c.1117C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2060811-C-A
• chr16-2060811-C-G
• chr16-2060811-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000548.5(TSC2):​c.1117C>A​(p.Gln373Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q373P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense, splice_region
• Scores: Splicing: ADA: 0.8169
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.99
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2060812-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 570588.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.1117C>A	p.Gln373Lys	missense splice_region	Exon 11 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.1117C>A	p.Gln373Lys	missense splice_region	Exon 11 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.1117C>A	p.Gln373Lys	missense splice_region	Exon 11 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.1117C>A	p.Gln373Lys	missense splice_region	Exon 11 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.1117C>A	p.Gln373Lys	missense splice_region	Exon 11 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.1117C>A	p.Gln373Lys	missense splice_region	Exon 11 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1

Oct 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant disrupts the p.Gln373 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been observed in individuals with TSC2-related conditions (PMID: 18854862; Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 1061060). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 373 of the TSC2 protein (p.Gln373Lys).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	-0.019	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.012	D
Polyphen		0.95	P
Vest4		0.51
MutPred		0.34		Gain of ubiquitination at Q373 (P = 0.0258)
MVP		0.93
ClinPred		0.92	D
GERP RS		4.6
Varity_R		0.54
gMVP		0.46
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.82
dbscSNV1_RF	Benign	0.60
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: rs45458694; hg19: chr16-2110812;