Genetic Variant TSC2:p.Glu1573Asp (chr16-2086249-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_000548.5(TSC2):c.4719G>C(p.Glu1573Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. E1573Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.275

Publications

0 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

tuberous sclerosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
tuberous sclerosis 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
lymphangioleiomyomatosis
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
tuberous sclerosis complex
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TSC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 38 uncertain in NM_000548.5

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSC2	NM_000548.5	MANE Select	c.4719G>C	p.Glu1573Asp	missense	Exon 37 of 42	NP_000539.2
TSC2	NM_001406663.1		c.4716G>C	p.Glu1572Asp	missense	Exon 37 of 42	NP_001393592.1
TSC2	NM_001114382.3		c.4650G>C	p.Glu1550Asp	missense	Exon 36 of 41	NP_001107854.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSC2	ENST00000219476.9	TSL:5 MANE Select	c.4719G>C	p.Glu1573Asp	missense	Exon 37 of 42	ENSP00000219476.3
TSC2	ENST00000350773.9	TSL:1	c.4650G>C	p.Glu1550Asp	missense	Exon 36 of 41	ENSP00000344383.4
TSC2	ENST00000401874.7	TSL:1	c.4518G>C	p.Glu1506Asp	missense	Exon 35 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Benign

0.040

Eigen_PC

Benign

-0.027

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.60

MetaSVM

Uncertain

0.57

MutationAssessor

Benign

1.1

PhyloP100

0.28

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.0

REVEL

Pathogenic

0.70

Sift

Benign

0.051

Sift4G

Benign

0.21

Polyphen

0.99

Vest4

0.64

MutPred

0.56

Loss of stability (P = 0.1684)

MVP

0.94

ClinPred

0.92

GERP RS

0.20

Varity_R

0.61

gMVP

0.52

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over