16-2088095-C-T

Variant names:

• chr16-2088095-C-T
• rs45517391
• NM_000548.5:c.5116C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM1 BP4_Moderate BP6 BS1 BS2

The NM_000548.5(TSC2):​c.5116C>T​(p.Arg1706Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,612,878 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1706L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (1 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:11 O:1
• Conservation: PhyloP100: 3.10
• Publications: 15 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 -9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 30 uncertain in NM_000548.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.16267908).
• BP6: Variant 16-2088095-C-T is Benign according to our data. Variant chr16-2088095-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 49912.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000289 (44/152302) while in subpopulation AFR AF = 0.000481 (20/41564). AF 95% confidence interval is 0.000319. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 44 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.5116C>T	p.Arg1706Cys	missense	Exon 40 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.5113C>T	p.Arg1705Cys	missense	Exon 40 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.5047C>T	p.Arg1683Cys	missense	Exon 39 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.5116C>T	p.Arg1706Cys	missense	Exon 40 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.5047C>T	p.Arg1683Cys	missense	Exon 39 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.4915C>T	p.Arg1639Cys	missense	Exon 38 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000296 AC: 74 AN: 250408 AF XY: 0.000295

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000381

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000409 AC: 598 AN: 1460576 Hom.: 1 Cov.: 32 AF XY: 0.000413 AC XY: 300 AN XY: 726624

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000514 AC: 23 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52152

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000496 AC: 551 AN: 1111990

Other (OTH) AF: 0.000265 AC: 16 AN: 60380

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74464

African (AFR) AF: 0.000481 AC: 20 AN: 41564

American (AMR) AF: 0.000261 AC: 4 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68016

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

Alfa AF: 0.000795 Hom.: 0

Bravo AF: 0.000287

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000218

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	3	Tuberous sclerosis 2 (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	1	not provided (2)
-	1	-	See cases (1)
-	-	1	Tuberous sclerosis syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.8	L
PhyloP100		3.1
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.46
MVP		0.89
ClinPred		0.059	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.56
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45517391; hg19: chr16-2138096; COSMIC: COSV106054119;