rs45517382

Variant names:

• chr16-2086834-A-G
• rs45517382
• NM_000548.5:c.4952A>G

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000548.5(TSC2):​c.4952A>G​(p.Asn1651Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000329791: Published functional studies demonstrate a damaging effect as N1651S impairs the ability of tuberin to act as a GTPase activating protein (Tee et al., 2003); PMID:18032745; SCV003839177: Functional studies have demonstrated that this sequence change impacts the function of the TSC2 protein (PMID:12906785, 18411301, 14718525, 18550814, 27078846).; SCV000644583: Experimental studies have shown that this missense change affects TSC2 function (PMID:12906785, 14718525, 18411301, 18550814, 27078846).; SCV002642642: In one other study, this mutation was shown to impair the ability of tuberin to act as a GTPase enhancing protein (Tee AR et al. Curr. Biol., 2003 Aug;13:1259-68).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1651D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.42
• Publications: 11 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: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000329791: Published functional studies demonstrate a damaging effect as N1651S impairs the ability of tuberin to act as a GTPase activating protein (Tee et al., 2003); PMID: 18032745; SCV003839177: Functional studies have demonstrated that this sequence change impacts the function of the TSC2 protein (PMID: 12906785, 18411301, 14718525, 18550814, 27078846).; SCV000644583: Experimental studies have shown that this missense change affects TSC2 function (PMID: 12906785, 14718525, 18411301, 18550814, 27078846).; SCV002642642: In one other study, this mutation was shown to impair the ability of tuberin to act as a GTPase enhancing protein (Tee AR et al. Curr. Biol., 2003 Aug;13:1259-68).
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 34 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2086833-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2032747.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 16-2086834-A-G is Pathogenic according to our data. Variant chr16-2086834-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 49335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.4952A>G	p.Asn1651Ser	missense	Exon 38 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.4949A>G	p.Asn1650Ser	missense	Exon 38 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.4883A>G	p.Asn1628Ser	missense	Exon 37 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.4952A>G	p.Asn1651Ser	missense	Exon 38 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.4883A>G	p.Asn1628Ser	missense	Exon 37 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.4751A>G	p.Asn1584Ser	missense	Exon 36 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	1.5	L
PhyloP100		7.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.81		Gain of disorder (P = 0.0551)
MVP		0.94
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.76
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 1

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

Other links and lift over

dbSNP: rs45517382; hg19: chr16-2136835; COSMIC: COSV51913564;