chr16-2058842-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_000548.5(TSC2):c.944C>T(p.Ser315Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,607,022 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S315A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 7.52

Publications

6 publications found

Variant links:

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

TSC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 16-2058842-C-T is Benign according to our data. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173. Variant chr16-2058842-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187173.

BS2

High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.944C>T	p.Ser315Leu	missense_variant	Exon 10 of 42	ENST00000219476.9	NP_000539.2	P49815-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 link	c.944C>T	p.Ser315Leu	missense_variant	Exon 10 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000840

AC:

AN:

238044

AF XY:

0.0000156

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000187

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1454806

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

722832

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.00

AC:

AN:

43766

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25884

East Asian (EAS)

AF:

0.00

AC:

AN:

39598

South Asian (SAS)

AF:

0.00

AC:

AN:

84542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52838

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1108798

Other (OTH)

AF:

0.0000332

AC:

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68048

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000170

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Uncertain:1Benign:1

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tuberous sclerosis syndrome

Uncertain:1

Sep 09, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces serine with leucine at codon 315 of the TSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has been identified in 2/238044 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Apr 28, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22703879) -

Hereditary cancer-predisposing syndrome

Benign:1

Mar 15, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

D;.;.;.;.;.;.;.;.;.;.;.;T;.;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.60

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.2

M;.;.;.;M;M;.;.;.;M;.;M;.;.;.

PhyloP100

7.5

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.5

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.0030

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

Sift4G

Uncertain

0.0060

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

Polyphen

1.0

D;.;.;.;D;D;.;.;D;D;.;.;.;.;.

Vest4

0.78

MutPred

0.36

Loss of disorder (P = 0.004);Loss of disorder (P = 0.004);Loss of disorder (P = 0.004);.;Loss of disorder (P = 0.004);Loss of disorder (P = 0.004);Loss of disorder (P = 0.004);Loss of disorder (P = 0.004);.;Loss of disorder (P = 0.004);Loss of disorder (P = 0.004);Loss of disorder (P = 0.004);Loss of disorder (P = 0.004);Loss of disorder (P = 0.004);.;

MVP

0.84

ClinPred

0.94

GERP RS

5.1

Varity_R

0.48

gMVP

0.55

Mutation Taster

=65/35

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over