rs1167258871

Positions:

• chr16-2071914-C-G
• chr16-2071914-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000548.5(TSC2):​c.2077C>G​(p.Leu693Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,439,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. L693P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.31

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2071915-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.32876605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.2077C>G	p.Leu693Val	missense_variant	19/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.2077C>G	p.Leu693Val	missense_variant	19/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1439320 Hom.: 0 Cov.: 33 AF XY: 0.00000280 AC XY: 2 AN XY: 713832

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 26, 2023

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 693 of the TSC2 protein (p.Leu693Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1051118). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function with a negative predictive value of 95%. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2024

The p.L693V variant (also known as c.2077C>G), located in coding exon 18 of the TSC2 gene, results from a C to G substitution at nucleotide position 2077. The leucine at codon 693 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Benign	0.91	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.54	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.59
Sift	Benign	0.43	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.31	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.99	D;.;.;.;D;P;.;.;P;P;.;.;.;.;.
Vest4		0.65
MutPred		0.48		Gain of MoRF binding (P = 0.099);Gain of MoRF binding (P = 0.099);Gain of MoRF binding (P = 0.099);.;Gain of MoRF binding (P = 0.099);Gain of MoRF binding (P = 0.099);Gain of MoRF binding (P = 0.099);Gain of MoRF binding (P = 0.099);.;Gain of MoRF binding (P = 0.099);Gain of MoRF binding (P = 0.099);Gain of MoRF binding (P = 0.099);Gain of MoRF binding (P = 0.099);Gain of MoRF binding (P = 0.099);.;
MVP		0.81
ClinPred		0.44	T
GERP RS		3.5
Varity_R		0.13
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1167258871; hg19: chr16-2121915;