rs45517295

Variant names:

• chr16-2080242-C-T
• rs45517295
• NM_000548.5:c.3475C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2080242-C-T
• chr16-2080242-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000548.5(TSC2):​c.3475C>T​(p.Arg1159Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,612,962 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1159Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:2
• Conservation: PhyloP100: 1.86
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071338713).
• BP6: Variant 16-2080242-C-T is Benign according to our data. Variant chr16-2080242-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000256 (39/152360) while in subpopulation EAS AF = 0.00502 (26/5182). AF 95% confidence interval is 0.00352. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 39 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.3475C>T	p.Arg1159Trp	missense	Exon 30 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.3472C>T	p.Arg1158Trp	missense	Exon 30 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.3475C>T	p.Arg1159Trp	missense	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.3475C>T	p.Arg1159Trp	missense	Exon 30 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.3475C>T	p.Arg1159Trp	missense	Exon 30 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.3343C>T	p.Arg1115Trp	missense	Exon 29 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000428 AC: 107 AN: 249822 AF XY: 0.000383

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00529

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000191 AC: 279 AN: 1460602 Hom.: 0 Cov.: 32 AF XY: 0.000186 AC XY: 135 AN XY: 726602

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

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

East Asian (EAS) AF: 0.00489 AC: 194 AN: 39700

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111994

Other (OTH) AF: 0.000729 AC: 44 AN: 60382

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.000268 AC XY: 20 AN XY: 74500

African (AFR) AF: 0.000120 AC: 5 AN: 41586

American (AMR) AF: 0.000261 AC: 4 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00502 AC: 26 AN: 5182

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000303 Hom.: 0

Bravo AF: 0.000314

ExAC AF: 0.000404 AC: 49

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Tuberous sclerosis 2 (4)
-	-	3	not specified (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (1)
-	-	1	TSC2-related disorder (1)
-	-	1	Tuberous sclerosis syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.9
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.018	D
Polyphen		0.98	D
Vest4		0.43
MVP		0.73
ClinPred		0.024	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066
gMVP		0.26
Mutation Taster		=92/8	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: rs45517295; hg19: chr16-2130243; COSMIC: COSV54771898;