Genetic Variant NM_000548.5:c.1378G>A (chr16-2062988-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000548.5(TSC2):c.1378G>A(p.Ala460Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000723 in 1,551,020 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts 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. A460P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00075 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00072 ( 3 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24O:2

Conservation

PhyloP100: 7.29

Publications

20 publications found

Variant links:

COSMIC-nc: COSV54776675

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

TSC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 36 uncertain in NM_000548.5

BP4

Computational evidence support a benign effect (MetaRNN=0.009741932).

BP6

Variant 16-2062988-G-A is Benign according to our data. Variant chr16-2062988-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000748 (114/152350) while in subpopulation NFE AF = 0.0005 (34/68026). AF 95% confidence interval is 0.000368. There are 1 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 114 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSC2	NM_000548.5	MANE Select	c.1378G>A	p.Ala460Thr	missense	Exon 14 of 42	NP_000539.2	P49815-1
TSC2	NM_001406663.1		c.1378G>A	p.Ala460Thr	missense	Exon 14 of 42	NP_001393592.1	A0A2R8Y6C9
TSC2	NM_001114382.3		c.1378G>A	p.Ala460Thr	missense	Exon 14 of 41	NP_001107854.1	P49815-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSC2	ENST00000219476.9	TSL:5 MANE Select	c.1378G>A	p.Ala460Thr	missense	Exon 14 of 42	ENSP00000219476.3	P49815-1
TSC2	ENST00000350773.9	TSL:1	c.1378G>A	p.Ala460Thr	missense	Exon 14 of 41	ENSP00000344383.4	P49815-4
TSC2	ENST00000401874.7	TSL:1	c.1378G>A	p.Ala460Thr	missense	Exon 14 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00125

AC:

194

AN:

155816

AF XY:

0.00134

show subpopulations

Gnomad AFR exome

AF:

0.000229

Gnomad AMR exome

AF:

0.000243

Gnomad ASJ exome

AF:

0.0131

Gnomad EAS exome

AF:

0.0000885

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000733

Gnomad OTH exome

AF:

0.00612

GnomAD4 exome

AF:

0.000721

AC:

1008

AN:

1398670

Hom.:

Cov.:

AF XY:

0.000768

AC XY:

530

AN XY:

689880

show subpopulations

African (AFR)

AF:

0.0000317

AC:

AN:

31586

American (AMR)

AF:

0.000420

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.0149

AC:

374

AN:

25170

East Asian (EAS)

AF:

0.0000840

AC:

AN:

35730

South Asian (SAS)

AF:

0.000114

AC:

AN:

79222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48918

Middle Eastern (MID)

AF:

0.0108

AC:

AN:

5546

European-Non Finnish (NFE)

AF:

0.000417

AC:

450

AN:

1078832

Other (OTH)

AF:

0.00166

AC:

AN:

57966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

137

206

274

343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000748

AC:

114

AN:

152350

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41584

American (AMR)

AF:

0.000327

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000500

AC:

AN:

68026

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00126

Hom.:

Bravo

AF:

0.000869

ESP6500AA

AF:

0.000257

AC:

ESP6500EA

AF:

0.00108

AC:

ExAC

AF:

0.000872

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

Tuberous sclerosis 2 (6)

not provided (4)

Tuberous sclerosis syndrome (5)

Hereditary cancer-predisposing syndrome (2)

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

0.089

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.0097

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.6

PhyloP100

7.3

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.43

REVEL

Uncertain

0.56

Sift

Benign

0.41

Sift4G

Benign

0.59

Polyphen

1.0

Vest4

0.65

MVP

0.81

ClinPred

0.060

GERP RS

5.2

PromoterAI

0.0015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.079

gMVP

0.17

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over