16-2061965-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000548.5(TSC2):c.1214A>T(p.Glu405Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. E405Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.61

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.1214A>T	p.Glu405Val	missense_variant	12/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.1214A>T	p.Glu405Val	missense_variant	12/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 15, 2016

A variant of uncertain significance has been identified in the TSC2 gene. The c.1214 A>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1214 A>T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Several in-silico splice prediction models predict that c.1214 A>T creates a cryptic splice donor site for exon 12, which may lead to abnormal gene splicing. If c.1214 A>T does not alter splicing, it will result in the E405V missense change. The E405V variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size, and/or other properties. This substitution occurs at an amino acid position where amino acids with similar properties to Glutamic acid are tolerated across species. Missense variants in nearby residues (Y407D, L410R) have been reported in the Human Gene Mutation Database in association with tuberous sclerosis (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	35
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.4	M;.;.;.;M;M;.;.;.;M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.2	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0060	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.0070	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.79
MutPred		0.53		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);.;Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);.;Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);.;
MVP		0.85
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		1.0		Position offset: -2
DS_DL_spliceai		0.91		Position offset: 43

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057518321; hg19: chr16-2111966;