rs146734084

Variant names:

• chr16-2080334-G-A
• rs146734084
• NM_000548.5:c.3567G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2080334-G-A
• chr16-2080334-G-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000548.5(TSC2):​c.3567G>A​(p.Leu1189Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000479 in 1,460,300 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 Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 2.81
• Publications: 0 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 16-2080334-G-A is Benign according to our data. Variant chr16-2080334-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468023.
• BP7: Synonymous conserved (PhyloP=2.81 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 70 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.3567G>A	p.Leu1189Leu	synonymous	Exon 30 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.3564G>A	p.Leu1188Leu	synonymous	Exon 30 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.3567G>A	p.Leu1189Leu	synonymous	Exon 30 of 41	NP_001107854.1	P49815-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.3567G>A	p.Leu1189Leu	synonymous	Exon 30 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.3567G>A	p.Leu1189Leu	synonymous	Exon 30 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.3435G>A	p.Leu1145Leu	synonymous	Exon 29 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000401 AC: 10 AN: 249502 AF XY: 0.0000369

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: 0.0000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1460300 Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33 AN XY: 726458

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

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: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52110

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5606

European-Non Finnish (NFE) AF: 0.0000603 AC: 67 AN: 1111968

Other (OTH) AF: 0.0000166 AC: 1 AN: 60350

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Tuberous sclerosis 2 (3)
-	-	2	not provided (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	5.6
DANN	Benign	0.36
PhyloP100		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs146734084; hg19: chr16-2130335;