rs45490792

Variant names:

• chr16-2071616-T-A
• rs45490792
• NM_000548.5:c.1946T>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2071616-T-A
• chr16-2071616-T-C
• chr16-2071616-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_000548.5(TSC2):​c.1946T>A​(p.Met649Lys) variant causes a missense, splice region 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. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M649I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense, splice_region
• Scores: Splicing: ADA: 0.0006659
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0110
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2071783-GG-AA is described in ClinVar as Pathogenic. ClinVar VariationId is 3774500.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.106638044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1946T>A	p.Met649Lys	missense_variant, splice_region_variant	Exon 18 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1946T>A	p.Met649Lys	missense_variant, splice_region_variant	Exon 18 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	0.00020	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	12
DANN	Benign	0.61
DEOGEN2	Uncertain	0.42	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-1.0	N;.;.;.;N;N;.;.;.;N;.;N;.;.;.
PhyloP100		0.011
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.82	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.42
Sift	Benign	0.88	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.67	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.022	B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.40
MutPred		0.68		Gain of solvent accessibility (P = 0.0038);Gain of solvent accessibility (P = 0.0038);Gain of solvent accessibility (P = 0.0038);.;Gain of solvent accessibility (P = 0.0038);Gain of solvent accessibility (P = 0.0038);Gain of solvent accessibility (P = 0.0038);Gain of solvent accessibility (P = 0.0038);.;Gain of solvent accessibility (P = 0.0038);Gain of solvent accessibility (P = 0.0038);Gain of solvent accessibility (P = 0.0038);Gain of solvent accessibility (P = 0.0038);Gain of solvent accessibility (P = 0.0038);.;
MVP		0.87
ClinPred		0.054	T
GERP RS		-3.8
Varity_R		0.079
gMVP		0.29
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00067
dbscSNV1_RF	Benign	0.17
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: rs45490792; hg19: chr16-2121617;