rs45517323

Variant names:

• chr16-2083797-G-A
• rs45517323
• NM_000548.5:c.3986G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2083797-G-A
• chr16-2083797-G-C
• chr16-2083797-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000548.5(TSC2):​c.3986G>A​(p.Arg1329His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,611,334 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. R1329C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (59 hom., cov: 34)
  • Exomes 𝑓: 0.0024 (60 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25 O:2
• Conservation: PhyloP100: -0.101
• Publications: 18 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=0.0023801625).
• BP6: Variant 16-2083797-G-A is Benign according to our data. Variant chr16-2083797-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

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.3986G>A	p.Arg1329His	missense	Exon 33 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.3983G>A	p.Arg1328His	missense	Exon 33 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.3917G>A	p.Arg1306His	missense	Exon 32 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.3986G>A	p.Arg1329His	missense	Exon 33 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.3917G>A	p.Arg1306His	missense	Exon 32 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.3785G>A	p.Arg1262His	missense	Exon 31 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2381 AN: 152198 Hom.: 59 Cov.: 34

Gnomad AFR AF: 0.0489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00667

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00535 AC: 1313 AN: 245202 AF XY: 0.00413

Gnomad AFR exome AF: 0.0535

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.000913

Gnomad EAS exome AF: 0.000605

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00318

GnomAD4 exome AF: 0.00237 AC: 3458 AN: 1459018 Hom.: 60 Cov.: 32 AF XY: 0.00208 AC XY: 1506 AN XY: 725626

African (AFR) AF: 0.0524 AC: 1753 AN: 33470

American (AMR) AF: 0.00278 AC: 124 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.000614 AC: 16 AN: 26040

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39656

South Asian (SAS) AF: 0.000152 AC: 13 AN: 85802

European-Finnish (FIN) AF: 0.00996 AC: 517 AN: 51900

Middle Eastern (MID) AF: 0.00192 AC: 11 AN: 5736

European-Non Finnish (NFE) AF: 0.000696 AC: 774 AN: 1111562

Other (OTH) AF: 0.00393 AC: 237 AN: 60310

GnomAD4 genome AF: 0.0157 AC: 2389 AN: 152316 Hom.: 59 Cov.: 34 AF XY: 0.0153 AC XY: 1143 AN XY: 74472

African (AFR) AF: 0.0489 AC: 2034 AN: 41558

American (AMR) AF: 0.00666 AC: 102 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0126 AC: 134 AN: 10632

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68018

Other (OTH) AF: 0.0156 AC: 33 AN: 2116

Alfa AF: 0.00565 Hom.: 36

Bravo AF: 0.0172

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0476 AC: 208

ESP6500EA AF: 0.000699 AC: 6

ExAC AF: 0.00609 AC: 734

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (8)
-	-	6	not provided (6)
-	-	6	Tuberous sclerosis 2 (6)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Tuberous sclerosis syndrome (3)
-	-	1	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (1)
-	-	1	Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	8.7
DANN	Benign	0.96
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.034	N
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.10
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.17	N
REVEL	Uncertain	0.43
Sift	Benign	0.043	D
Sift4G	Uncertain	0.052	T
Polyphen		0.98	D
Vest4		0.089
MVP		0.77
ClinPred		0.0047	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.26
Mutation Taster		=100/0	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: rs45517323; hg19: chr16-2133798; COSMIC: COSV51920598; COSMIC: COSV51920598;