16-2072337-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000548.5(TSC2):c.2194C>G(p.Gln732Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. Q732H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.71

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 17 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.2194C>G	p.Gln732Glu	missense_variant	20/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.2194C>G	p.Gln732Glu	missense_variant	20/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	23
Dann	Benign	0.97
DEOGEN2	Uncertain	0.43	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.013
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.97	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
MutationTaster	Benign	0.83	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.83	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.42
Sift	Benign	0.35	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.28	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.65	P;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.65
MutPred		0.47		Loss of catalytic residue at Q732 (P = 0.0657);Loss of catalytic residue at Q732 (P = 0.0657);Loss of catalytic residue at Q732 (P = 0.0657);.;Loss of catalytic residue at Q732 (P = 0.0657);Loss of catalytic residue at Q732 (P = 0.0657);Loss of catalytic residue at Q732 (P = 0.0657);Loss of catalytic residue at Q732 (P = 0.0657);.;Loss of catalytic residue at Q732 (P = 0.0657);Loss of catalytic residue at Q732 (P = 0.0657);Loss of catalytic residue at Q732 (P = 0.0657);Loss of catalytic residue at Q732 (P = 0.0657);Loss of catalytic residue at Q732 (P = 0.0657);.;
MVP		0.77
ClinPred		0.60	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs45517216; hg19: chr16-2122338;