chr16-2083815-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000548.5(TSC2):c.4004G>A(p.Arg1335Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R1335M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Consequence

TSC2
NM_000548.5 missense, splice_region

Scores

Splicing: ADA: 0.5260

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.52

Publications

1 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20290306).

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.4004G>A	p.Arg1335Lys	missense splice_region	Exon 33 of 42	NP_000539.2
TSC2	NM_001406663.1		c.4001G>A	p.Arg1334Lys	missense splice_region	Exon 33 of 42	NP_001393592.1
TSC2	NM_001114382.3		c.3935G>A	p.Arg1312Lys	missense splice_region	Exon 32 of 41	NP_001107854.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSC2	ENST00000219476.9	TSL:5 MANE Select	c.4004G>A	p.Arg1335Lys	missense splice_region	Exon 33 of 42	ENSP00000219476.3
TSC2	ENST00000350773.9	TSL:1	c.3935G>A	p.Arg1312Lys	missense splice_region	Exon 32 of 41	ENSP00000344383.4
TSC2	ENST00000401874.7	TSL:1	c.3803G>A	p.Arg1268Lys	missense splice_region	Exon 31 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

243282

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Uncertain:1

Mar 18, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine with lysine at codon 1335 of the TSC2 protein (p.Arg1335Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TSC2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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

May 02, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R1335K variant (also known as c.4004G>A), located in coding exon 32 of the TSC2 gene, results from a G to A substitution at nucleotide position 4004. The arginine at codon 1335 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

Eigen

Benign

0.11

Eigen_PC

Benign

0.080

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.20

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

1.8

PhyloP100

2.5

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.56

REVEL

Uncertain

0.41

Sift

Benign

0.19

Sift4G

Benign

0.42

Polyphen

0.93

Vest4

0.38

MutPred

0.15

Gain of ubiquitination at R1335 (P = 0.0011)

MVP

0.96

ClinPred

0.61

GERP RS

4.1

Varity_R

0.17

gMVP

0.33

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.53

dbscSNV1_RF

Benign

0.54

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over