rs796053476

Variant names:

• chr16-2080332-C-G
• rs796053476
• NM_000548.5:c.3565C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-2080332-C-G
• chr16-2080332-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000548.5(TSC2):​c.3565C>G​(p.Leu1189Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1189L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.704
• 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

  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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15336543).
• BP6: Variant 16-2080332-C-G is Benign according to our data. Variant chr16-2080332-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 207678.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.3565C>G	p.Leu1189Val	missense	Exon 30 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.3562C>G	p.Leu1188Val	missense	Exon 30 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.3565C>G	p.Leu1189Val	missense	Exon 30 of 41	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.3565C>G	p.Leu1189Val	missense	Exon 30 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.3565C>G	p.Leu1189Val	missense	Exon 30 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.3433C>G	p.Leu1145Val	missense	Exon 29 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460348 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726474

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111976

Other (OTH) AF: 0.0000166 AC: 1 AN: 60354

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Tuberous sclerosis 2 (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	-0.0022	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.70
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.49	N
REVEL	Uncertain	0.60
Sift	Benign	0.23	T
Sift4G	Benign	0.38	T
Polyphen		0.98	D
Vest4		0.50
MutPred		0.51		Loss of helix (P = 0.0376)
MVP		0.69
ClinPred		0.093	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.063
gMVP		0.49
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs796053476; hg19: chr16-2130333;