rs45517319

Variant names:

• chr16-2083700-G-A
• rs45517319
• NM_000548.5:c.3889G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2083700-G-A
• chr16-2083700-G-T
• chr16-2083700-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000548.5(TSC2):​c.3889G>A​(p.Ala1297Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,583,898 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. A1297V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (13 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:24 O:2
• Conservation: PhyloP100: 2.52
• Publications: 25 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007479131).
• BP6: Variant 16-2083700-G-A is Benign according to our data. Variant chr16-2083700-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41736.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0022 (335/152290) while in subpopulation NFE AF = 0.00344 (234/68006). AF 95% confidence interval is 0.00308. There are 2 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 335 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.3889G>A	p.Ala1297Thr	missense	Exon 33 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.3886G>A	p.Ala1296Thr	missense	Exon 33 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.3820G>A	p.Ala1274Thr	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.3889G>A	p.Ala1297Thr	missense	Exon 33 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.3820G>A	p.Ala1274Thr	missense	Exon 32 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.3688G>A	p.Ala1230Thr	missense	Exon 31 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 335 AN: 152172 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00344

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00280 AC: 565 AN: 201906 AF XY: 0.00292

Gnomad AFR exome AF: 0.000811

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.0000652

Gnomad FIN exome AF: 0.00490

Gnomad NFE exome AF: 0.00376

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00331 AC: 4742 AN: 1431608 Hom.: 13 Cov.: 32 AF XY: 0.00324 AC XY: 2300 AN XY: 709082

African (AFR) AF: 0.000963 AC: 32 AN: 33222

American (AMR) AF: 0.000992 AC: 39 AN: 39308

Ashkenazi Jewish (ASJ) AF: 0.00338 AC: 86 AN: 25434

East Asian (EAS) AF: 0.0000775 AC: 3 AN: 38696

South Asian (SAS) AF: 0.00238 AC: 195 AN: 82022

European-Finnish (FIN) AF: 0.00330 AC: 165 AN: 50026

Middle Eastern (MID) AF: 0.000524 AC: 3 AN: 5726

European-Non Finnish (NFE) AF: 0.00370 AC: 4062 AN: 1097832

Other (OTH) AF: 0.00265 AC: 157 AN: 59342

GnomAD4 genome AF: 0.00220 AC: 335 AN: 152290 Hom.: 2 Cov.: 33 AF XY: 0.00215 AC XY: 160 AN XY: 74470

African (AFR) AF: 0.000746 AC: 31 AN: 41556

American (AMR) AF: 0.000849 AC: 13 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4830

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00344 AC: 234 AN: 68006

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00314 Hom.: 6

Bravo AF: 0.00203

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00161 AC: 7

ESP6500EA AF: 0.00408 AC: 35

ExAC AF: 0.00219 AC: 262

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	8	not provided (9)
-	1	6	Tuberous sclerosis 2 (7)
-	-	4	not specified (5)
-	-	3	Tuberous sclerosis syndrome (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0075	T
MetaSVM	Uncertain	-0.097	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.49
Sift	Benign	0.093	T
Sift4G	Benign	0.52	T
Polyphen		1.0	D
Vest4		0.21
MVP		0.97
ClinPred		0.0079	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.038
gMVP		0.44
Mutation Taster		=100/0	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: rs45517319; hg19: chr16-2133701; COSMIC: COSV54767486; COSMIC: COSV54767486;