NM_000548.5:c.4662G>C

Variant names:

• chr16-2085322-G-C
• rs137854880
• NM_000548.5:c.4662G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000548.5(TSC2):​c.4662G>C​(p.Gln1554His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1554P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TSC2 NM_000548.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance no assertion criteria provided U:1 O:1
• Conservation: PhyloP100: 9.66
• Publications: 3 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 39 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2085321-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 49866.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.4662G>C	p.Gln1554His	missense splice_region	Exon 36 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.4659G>C	p.Gln1553His	missense splice_region	Exon 36 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.4593G>C	p.Gln1531His	missense splice_region	Exon 35 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.4662G>C	p.Gln1554His	missense splice_region	Exon 36 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.4593G>C	p.Gln1531His	missense splice_region	Exon 35 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.4461G>C	p.Gln1487His	missense splice_region	Exon 34 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

TSC2-related disorder Uncertain:1

Feb 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TSC2 c.4662G>C variant is predicted to result in the amino acid substitution p.Gln1554His. This variant occurs at the final nucleotide position of exon 36 and splicing prediction programs predict a splicing defect at the consensus donor site (SpliceAI, Jaganathan K, et al. 2019. PubMed ID: 30661751). This variant was reported as probably pathogenic in an individual with suspected tuberous sclerosis complex (TSC); however, detailed clinical information was not provided (Table S2, Hoogeveen-Westerveld et al. 2013. PubMed ID: 22903760). In addition, functional analyses of this variant showed that it led to an increased but "intermediate" effect when compared to wild type and a known pathogenic TSC2 variant (Table S1, Hoogeveen-Westerveld et al. 2013. PubMed ID: 22903760). This variant has not been reported in large population database, indicating this variant is rare. Of note, a different nucleotide variant (c.4662G>T) leading to the same amino acid change (p. Gln1554His) was reported as de novo in a patient with TSC (Rendtorff et al. 2005. PubMed ID: 16114042). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Tuberous sclerosis syndrome Other:1

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		9.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.91		Loss of helix (P = 0.079)
MVP		0.99
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.95
gMVP		0.97
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.58		Position offset: 23
DS_DL_spliceai		0.85		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137854880; hg19: chr16-2135323;