16-2079171-T-G

Position:

• chr16-2079171-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000548.5(TSC2):​c.3106T>G​(p.Ser1036Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. S1036P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.11

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 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 chr16-2079171-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.3106T>G	p.Ser1036Ala	missense_variant	27/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.3106T>G	p.Ser1036Ala	missense_variant	27/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Invitae

Sep 21, 2021

This sequence change replaces serine with alanine at codon 1036 of the TSC2 protein (p.Ser1036Ala). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and alanine. 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. 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. ClinVar contains an entry for this variant (Variation ID: 207739). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (ExAC no frequency). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 10, 2018

p.Ser1036Ala (TCC>GCC): c.3106 T>G in exon 27 of the TSC2 gene (NM_000548.3)The Ser1036Ala missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Ser1036Ala in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. A different missense substitution at this same position (Ser1036Pro) has been reported in a family with seizures and mild features associated with tuberous sclerosis. This missense change was seen in both affected and unaffected family members, and only two of the affected individuals met clinical criteria for probable tuberous sclerosis (O'Connor et al., 2003). In vitro functional studies indicated that Ser1036Pro inactivates the TSC1-TSC2 complex without disrupting TSC1-TSC2 binding (Wentink et al., 2011; Hoogeveen-Westerveld et al., 2011). The Ser1036Ala amino acid substitution is non-conservative as a polar Serine residue is replaced by a non-polar Alanine residue. Ser1036Ala alters a conserved position in a region of the tuberin protein where other missense mutations have been reported in association with tuberous sclerosis. However, Ser1036Ala does not occur within known functional domains in which many pathogenic missense mutations have previously been identified (Northrup et al., 2011; Au et al., 2007). In addition, several in-silico algorithms predict it may be a benign change. Therefore, based on the currently available information, it is unclear whether Ser1036Ala is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.65	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	1.8	L;.;.;.;.;.;.;.;.;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.8	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Pathogenic	0.66
Sift	Benign	0.26	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.094	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.93	P;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.66
MutPred		0.42		Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);.;.;.;.;Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);.;.;.;.;.;
MVP		0.93
ClinPred		0.86	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.80

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: rs45517281; hg19: chr16-2129172;