NM_000548.5:c.2070C>A

Variant names:

• chr16-2071907-C-A
• rs558292668
• NM_000548.5:c.2070C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000548.5(TSC2):​c.2070C>A​(p.Phe690Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F690V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.473
• 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: 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 33 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage

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.2070C>A	p.Phe690Leu	missense	Exon 19 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.2070C>A	p.Phe690Leu	missense	Exon 19 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.2070C>A	p.Phe690Leu	missense	Exon 19 of 41	NP_001107854.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.2070C>A	p.Phe690Leu	missense	Exon 19 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.2070C>A	p.Phe690Leu	missense	Exon 19 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.2070C>A	p.Phe690Leu	missense	Exon 19 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1441534 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 715286

African (AFR) AF: 0.00 AC: 0 AN: 33122

American (AMR) AF: 0.00 AC: 0 AN: 42566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25656

East Asian (EAS) AF: 0.00 AC: 0 AN: 38746

South Asian (SAS) AF: 0.00 AC: 0 AN: 83426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102414

Other (OTH) AF: 0.00 AC: 0 AN: 59468

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Tuberous sclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.47
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.60
Sift	Benign	0.16	T
Sift4G	Benign	0.085	T
Polyphen		0.090	B
Vest4		0.55
MutPred		0.54		Gain of disorder (P = 0.0373)
MVP		0.86
ClinPred		0.81	D
GERP RS		0.74
Varity_R		0.55
gMVP		0.61
Mutation Taster		=69/31	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: rs558292668; hg19: chr16-2121908;