16-2083725-C-T

Variant names:

• chr16-2083725-C-T
• rs45517320
• NM_000548.5:c.3914C>T

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.3914C>T​(p.Pro1305Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,597,668 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. P1305S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0070 (15 hom., cov: 34)
  • Exomes 𝑓: 0.00072 (15 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24 O:2
• Conservation: PhyloP100: 0.288
• Publications: 17 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=0.005974084).
• BP6: Variant 16-2083725-C-T is Benign according to our data. Variant chr16-2083725-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.007 (1066/152288) while in subpopulation AFR AF = 0.0231 (961/41544). AF 95% confidence interval is 0.0219. There are 15 homozygotes in GnomAd4. There are 494 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1066 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.3914C>T	p.Pro1305Leu	missense	Exon 33 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.3911C>T	p.Pro1304Leu	missense	Exon 33 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.3845C>T	p.Pro1282Leu	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.3914C>T	p.Pro1305Leu	missense	Exon 33 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.3845C>T	p.Pro1282Leu	missense	Exon 32 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.3713C>T	p.Pro1238Leu	missense	Exon 31 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.00700 AC: 1065 AN: 152170 Hom.: 15 Cov.: 34

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

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: 0.0000735

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00189 AC: 421 AN: 222830 AF XY: 0.00146

Gnomad AFR exome AF: 0.0259

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000499

Gnomad OTH exome AF: 0.000359

GnomAD4 exome AF: 0.000716 AC: 1035 AN: 1445380 Hom.: 15 Cov.: 32 AF XY: 0.000625 AC XY: 448 AN XY: 717292

African (AFR) AF: 0.0237 AC: 791 AN: 33392

American (AMR) AF: 0.00175 AC: 73 AN: 41706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25694

East Asian (EAS) AF: 0.00 AC: 0 AN: 39176

South Asian (SAS) AF: 0.0000840 AC: 7 AN: 83344

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51066

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5742

European-Non Finnish (NFE) AF: 0.0000615 AC: 68 AN: 1105350

Other (OTH) AF: 0.00147 AC: 88 AN: 59910

GnomAD4 genome AF: 0.00700 AC: 1066 AN: 152288 Hom.: 15 Cov.: 34 AF XY: 0.00663 AC XY: 494 AN XY: 74454

African (AFR) AF: 0.0231 AC: 961 AN: 41544

American (AMR) AF: 0.00562 AC: 86 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

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: 0.0000735 AC: 5 AN: 68020

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00235 Hom.: 3

Bravo AF: 0.00812

ESP6500AA AF: 0.0208 AC: 91

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00229 AC: 275

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (9)
-	-	5	not provided (5)
-	-	5	Tuberous sclerosis 2 (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	0.070
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.29
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.41
Sift	Benign	0.19	T
Sift4G	Benign	0.45	T
Polyphen		1.0	D
Vest4		0.18
MVP		0.84
ClinPred		0.0091	T
GERP RS		-0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.060
gMVP		0.30
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: rs45517320; hg19: chr16-2133726; COSMIC: COSV51920592; COSMIC: COSV51920592;