16-2062988-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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 (★★).

Frequency

Genomes: 𝑓 0.00075 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00072 ( 3 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

1
10
8

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22O:2

Conservation

PhyloP100: 7.29
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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 [Likely_benign]. Clinvar id is 49660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062988-G-A is described in Lovd as [Benign]. Variant chr16-2062988-G-A is described in Lovd as [Pathogenic].
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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 114 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC2NM_000548.5 linkc.1378G>A p.Ala460Thr missense_variant Exon 14 of 42 ENST00000219476.9 NP_000539.2 P49815-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TSC2ENST00000219476.9 linkc.1378G>A p.Ala460Thr missense_variant Exon 14 of 42 5 NM_000548.5 ENSP00000219476.3 P49815-1

Frequencies

GnomAD3 genomes
AF:
0.000749
AC:
114
AN:
152232
Hom.:
1
Cov.:
33
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
GnomAD3 exomes
AF:
0.00125
AC:
194
AN:
155816
Hom.:
2
AF XY:
0.00134
AC XY:
110
AN XY:
82070
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 SAS exome
AF:
0.0000878
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.:
3
Cov.:
31
AF XY:
0.000768
AC XY:
530
AN XY:
689880
show subpopulations
Gnomad4 AFR exome
AF:
0.0000317
Gnomad4 AMR exome
AF:
0.000420
Gnomad4 ASJ exome
AF:
0.0149
Gnomad4 EAS exome
AF:
0.0000840
Gnomad4 SAS exome
AF:
0.000114
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000417
Gnomad4 OTH exome
AF:
0.00166
GnomAD4 genome
AF:
0.000748
AC:
114
AN:
152350
Hom.:
1
Cov.:
33
AF XY:
0.000752
AC XY:
56
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.0000240
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.0161
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000500
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00141
Hom.:
3
Bravo
AF:
0.000869
ESP6500AA
AF:
0.000257
AC:
1
ESP6500EA
AF:
0.00108
AC:
8
ExAC
AF:
0.000872
AC:
50
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:22Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:7Other:1
Apr 25, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.5% (46/8536) European chromosomes; ClinVar: 2 labs classify as LB. 3/5 pubs describe as nonpathogenic. -

Oct 07, 2021
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 21, 2015
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 28, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: TSC2 c.1378G>A (p.Ala460Thr) results in a non-conservative amino acid change located in the Tuberin, N-terminal domain of 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 0.0012 in 155816 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 18.11 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.1378G>A in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Tuberous sclerosis 2 Benign:6
Sep 20, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 05, 2020
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:4
Jan 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

TSC2: BS1 -

Nov 08, 2018
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25281918, 25637381, 21309039, 24728327, 19258292, 27884173) -

Nov 23, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Tuberous sclerosis syndrome Benign:3Other:1
Feb 12, 2018
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

-
Tuberous sclerosis database (TSC2)
Significance: not provided
Review Status: no classification provided
Collection Method: curation

- -

Jun 01, 2014
CSER _CC_NCGL, University of Washington
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: research

- -

Sep 23, 2024
All of Us Research Program, National Institutes of Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2
Aug 20, 2015
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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 10, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.089
BayesDel_addAF
Uncertain
0.068
T
BayesDel_noAF
Pathogenic
0.24
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.87
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.0097
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.18
T
MutationAssessor
Benign
1.6
L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-0.43
N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL
Uncertain
0.56
Sift
Benign
0.41
T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G
Benign
0.59
T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen
1.0
D;.;.;.;D;D;.;.;D;P;.;.;.;.;.
Vest4
0.65
MVP
0.81
ClinPred
0.060
T
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.079
gMVP
0.17

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137854154; hg19: chr16-2112989; COSMIC: COSV54776675; COSMIC: COSV54776675; API