16-2084327-C-T

Variant names:

• chr16-2084327-C-T
• rs45517328
• NM_000548.5:c.4105C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_000548.5(TSC2):​c.4105C>T​(p.Arg1369Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000402 in 1,612,600 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1369Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00042 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:16 O:1
• Conservation: PhyloP100: 1.26
• Publications: 9 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: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35132384).
• BP6: Variant 16-2084327-C-T is Benign according to our data. Variant chr16-2084327-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 49556.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000243 (37/152222) while in subpopulation NFE AF = 0.00047 (32/68028). AF 95% confidence interval is 0.000342. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 37 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.4105C>T	p.Arg1369Trp	missense	Exon 34 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.4102C>T	p.Arg1368Trp	missense	Exon 34 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.4036C>T	p.Arg1346Trp	missense	Exon 33 of 41	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.4105C>T	p.Arg1369Trp	missense	Exon 34 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.4036C>T	p.Arg1346Trp	missense	Exon 33 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.3904C>T	p.Arg1302Trp	missense	Exon 32 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152222 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000237 AC: 59 AN: 248644 AF XY: 0.000229

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000561

Gnomad NFE exome AF: 0.000376

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000418 AC: 611 AN: 1460378 Hom.: 0 Cov.: 33 AF XY: 0.000406 AC XY: 295 AN XY: 726466

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.000500 AC: 26 AN: 52020

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

European-Non Finnish (NFE) AF: 0.000511 AC: 568 AN: 1111962

Other (OTH) AF: 0.000199 AC: 12 AN: 60370

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152222 Hom.: 0 Cov.: 34 AF XY: 0.000229 AC XY: 17 AN XY: 74362

African (AFR) AF: 0.0000483 AC: 2 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000332 Hom.: 0

Bravo AF: 0.000185

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000190 AC: 23

EpiCase AF: 0.000109

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:16 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 02, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27601542, 26703369, 23514105, 25925381, 21309039)

Aug 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 17, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 01, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TSC2: BS2

Tuberous sclerosis 2 Benign:3

Jun 02, 2025

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tuberous sclerosis syndrome Benign:2 Other:1

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Aug 31, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Dec 18, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TSC2 c.4105C>T (p.Arg1369Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 248644 control chromosomes (gnomAD). The observed variant frequency is approximately 3.45 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.4105C>T in individuals affected with Tuberous Sclerosis Complex has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (Hoogeveen-Westerveld_2011). These results showed no damaging effect of this variant. The following publication has been ascertained in the context of this evaluation (PMID: 21309039). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as benign (n=4), likely benign (n=5), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:2

Jul 20, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

May 03, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

TSC2-related disorder Benign:1

Feb 17, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.8	L
PhyloP100		1.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.46
Sift	Benign	0.045	D
Sift4G	Benign	0.16	T
Polyphen		0.99	D
Vest4		0.62
MVP		0.96
ClinPred		0.13	T
GERP RS		-0.017
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.081
gMVP		0.32
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs45517328; hg19: chr16-2134328;