rs45517107

Positions:

• chr16-2054369-A-G
• chr16-2054369-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000548.5(TSC2):​c.410A>G​(p.His137Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 2.16

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.410A>G	p.His137Arg	missense_variant	5/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.410A>G	p.His137Arg	missense_variant	5/42	5	NM_000548.5	ENSP00000219476

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 21, 2020

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with tuberous sclerosis complex (PMID: 10570911). ClinVar contains an entry for this variant (Variation ID: 49283). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with arginine at codon 137 of the TSC2 protein (p.His137Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. 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. -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.41	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.3	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
MutationTaster	Benign	0.63	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.59
Sift	Benign	0.071	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.091	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.99	D;.;.;.;.;D;.;.;P;P;.;.;.;.;.
Vest4		0.68
MutPred		0.75		Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);.;Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);.;Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);.;
MVP		0.99
ClinPred		0.24	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.094
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs45517107; hg19: chr16-2104370; COSMIC: COSV54770370; COSMIC: COSV54770370;