chr16-2084328-G-A

Variant names:

• chr16-2084328-G-A
• rs587778738
• NM_000548.5:c.4106G>A
• TSC2 p.Arg1369Gln

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP6

The NM_000548.5(TSC2):c.4106G>A (p.Arg1369Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000753 (AC=11) in the gnomAD database across 1,460,376 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000298. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). 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.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: 34)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6 O:1
• Conservation: PhyloP100: 2.83
• Publications: 1 publications found

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000298 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TSC2 NM_000548.5	MANE Select	c.4106G>A p.Arg1369Gln	missense	Exon 34 of 42	Prot: NP_000539.2 UniProt:
	TSC2 NM_001406663.1		c.4103G>A p.Arg1368Gln	missense	Exon 34 of 42	Prot: NP_001393592.1 UniProt:
	TSC2 NM_001114382.3		c.4037G>A p.Arg1346Gln	missense	Exon 33 of 41	Prot: NP_001107854.1 UniProt:

TSC2 NM_000548.5

MANE Select

HGVSc / HGVSpc.4106G>Ap.Arg1369Gln

Exon rankExon 34 of 42

missense

Prot: NP_000539.2UniProt: P49815-1

TSC2 NM_001406663.1

HGVSc / HGVSpc.4103G>Ap.Arg1368Gln

Exon rankExon 34 of 42

missense

Prot: NP_001393592.1UniProt: A0A2R8Y6C9

TSC2 NM_001114382.3

HGVSc / HGVSpc.4037G>Ap.Arg1346Gln

Exon rankExon 33 of 41

missense

Prot: NP_001107854.1UniProt: P49815-4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TSC2 ENST00000219476.9	TSL:5MANE Select	c.4106G>A p.Arg1369Gln	missense	Exon 34 of 42	Prot: ENSP00000219476.3 UniProt:
	TSC2 ENST00000350773.9	TSL:1	c.4037G>A p.Arg1346Gln	missense	Exon 33 of 41	Prot: ENSP00000344383.4 UniProt:
	TSC2 ENST00000401874.7	TSL:1	c.3905G>A p.Arg1302Gln	missense	Exon 32 of 40	Prot: ENSP00000384468.2 UniProt:

TSC2 ENST00000219476.9

TSL:5MANE Select

HGVSc / HGVSpc.4106G>Ap.Arg1369Gln

Exon rankExon 34 of 42

missense

Prot: ENSP00000219476.3UniProt: P49815-1

TSC2 ENST00000350773.9

TSL:1

HGVSc / HGVSpc.4037G>Ap.Arg1346Gln

Exon rankExon 33 of 41

missense

Prot: ENSP00000344383.4UniProt: P49815-4

TSC2 ENST00000401874.7

TSL:1

HGVSc / HGVSpc.3905G>Ap.Arg1302Gln

Exon rankExon 32 of 40

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:34
GnomAD2 exomes	AF: 0.0000241	AC:6	Hom:	AN:248622	Cov:
GnomAD4 exome	AF: 0.00000753	AC:11	Hom:0	AN:1460376	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:34
TOPMed (Bravo)	AF: 0.0000453	AC:12	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000904	AC:3	Hom:0	AN:33202	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.000295	AC:	Hom:	AN:	Cov:
Korea4K (4,157 Koreans)	AF: 0.000138	AC:1	Hom:	AN:7234	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000670	AC:6	Hom:0	AN:8960	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000477	2	41958	0.0000299	2	66888
SCHEMA(Schizophrenia)	0.0000985	9	91412	0.0000555	9	162110

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	3	Tuberous sclerosis 2 (6)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	-	TSC2-related disorder (1)
-	-	1	Tuberous sclerosis syndrome (1)
-	-	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	13
AlphaMissense	Benign	0.064
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.95	D
FuncVEP CTI	Benign	0.0024
GPN-Star LLR	N/A	-3.2
GPN-Star score	N/A	3.2
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	-0.23	T
Mutation Taster	N/A	96/4	polymorphism
MutationAssessor	Benign	0.64	N
PhyloP100	Benign	2.8
popEVE	Benign	-3.0
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.44	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Uncertain	0.46
Sift	Benign	0.19	T
Sift4G	Benign	0.50	T
Varity_R	N/A	0.065
VESM-3B	Benign	-4.0

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.030	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

Other links and lift over

dbSNP: rs587778738;

hg19: chr16-2134329;

COSMIC: COSV105862579;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar