Genetic Variant TSC2:p.Arg1369Gln (chr16-2084328-GG-AA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_000548.5(TSC2):c.4106_4107delGGinsAA (p.Arg1369Gln) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R1369P: Uncertain_significance (ClinVar VariationId 3637231, 1 star); p.R1369Q: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 135386); p.R1369= (synonymous): Benign/Likely_benign (ClinVar VariationId 824599, 2 stars); p.R1369= (synonymous): Benign/Likely_benign (ClinVar VariationId 207681, 2 stars); p.R1369= (synonymous): Benign/Likely_benign (ClinVar VariationId 413698, 2 stars); p.R1369W: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 49556) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: not found (cov: 33)

Consequence

TSC2
NM_000548.5 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.83

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 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
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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new If you want to explore the variant's impact on the transcript NM_000548.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
TSC2 NM_000548.5	MANE Select	c.4106_4107delGGinsAA p.Arg1369Gln	missense	N/A	Prot: NP_000539.2 UniProt: P49815-1
TSC2 NM_001406663.1		c.4103_4104delGGinsAA p.Arg1368Gln	missense	N/A	Prot: NP_001393592.1 UniProt: A0A2R8Y6C9
TSC2 NM_001114382.3		c.4037_4038delGGinsAA p.Arg1346Gln	missense	N/A	Prot: NP_001107854.1 UniProt: P49815-4

TSC2 NM_000548.5

MANE Select

HGVSc / HGVSpc.4106_4107delGGinsAAp.Arg1369Gln

Exon rankN/A

missense

Prot: NP_000539.2UniProt: P49815-1

TSC2 NM_001406663.1

HGVSc / HGVSpc.4103_4104delGGinsAAp.Arg1368Gln

Exon rankN/A

missense

Prot: NP_001393592.1UniProt: A0A2R8Y6C9

TSC2 NM_001114382.3

HGVSc / HGVSpc.4037_4038delGGinsAAp.Arg1346Gln

Exon rankN/A

missense

Prot: NP_001107854.1UniProt: P49815-4

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
TSC2 ENST00000219476.9	TSL:5MANE Select	c.4106_4107delGGinsAA p.Arg1369Gln	missense	N/A	Prot: ENSP00000219476.3 UniProt: P49815-1
TSC2 ENST00000350773.9	TSL:1	c.4037_4038delGGinsAA p.Arg1346Gln	missense	N/A	Prot: ENSP00000344383.4 UniProt: P49815-4
TSC2 ENST00000401874.7	TSL:1	c.3905_3906delGGinsAA p.Arg1302Gln	missense	N/A	Prot: ENSP00000384468.2 UniProt: P49815-5

TSC2 ENST00000219476.9

TSL:5MANE Select

HGVSc / HGVSpc.4106_4107delGGinsAAp.Arg1369Gln

Exon rankN/A

missense

Prot: ENSP00000219476.3UniProt: P49815-1

TSC2 ENST00000350773.9

TSL:1

HGVSc / HGVSpc.4037_4038delGGinsAAp.Arg1346Gln

Exon rankN/A

missense

Prot: ENSP00000344383.4UniProt: P49815-4

TSC2 ENST00000401874.7

TSL:1

HGVSc / HGVSpc.3905_3906delGGinsAAp.Arg1302Gln

Exon rankN/A

missense

Prot: ENSP00000384468.2UniProt: P49815-5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	2.8

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence