rs1800742

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000548.5(TSC2):​c.1110G>A​(p.Gln370Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,538 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 9 hom., cov: 33)
Exomes 𝑓: 0.011 ( 113 hom. )

Consequence

TSC2
NM_000548.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:20O:1

Conservation

PhyloP100: 2.02
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.49).
BP6
Variant 16-2060804-G-A is Benign according to our data. Variant chr16-2060804-G-A is described in ClinVar as [Benign]. Clinvar id is 49141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2060804-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=2.02 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00814 (1240/152292) while in subpopulation NFE AF= 0.0115 (782/68030). AF 95% confidence interval is 0.0108. There are 9 homozygotes in gnomad4. There are 581 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1240 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC2NM_000548.5 linkc.1110G>A p.Gln370Gln synonymous_variant Exon 11 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.1110G>A p.Gln370Gln synonymous_variant Exon 11 of 42 5 NM_000548.5 ENSP00000219476.3 P49815-1

Frequencies

GnomAD3 genomes
AF:
0.00817
AC:
1243
AN:
152174
Hom.:
9
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00193
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00864
Gnomad ASJ
AF:
0.0346
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00683
Gnomad FIN
AF:
0.00433
Gnomad MID
AF:
0.0573
Gnomad NFE
AF:
0.0115
Gnomad OTH
AF:
0.0144
GnomAD3 exomes
AF:
0.0100
AC:
2511
AN:
250212
Hom.:
19
AF XY:
0.0101
AC XY:
1373
AN XY:
135582
show subpopulations
Gnomad AFR exome
AF:
0.00148
Gnomad AMR exome
AF:
0.00512
Gnomad ASJ exome
AF:
0.0335
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00549
Gnomad FIN exome
AF:
0.00603
Gnomad NFE exome
AF:
0.0140
Gnomad OTH exome
AF:
0.0162
GnomAD4 exome
AF:
0.0108
AC:
15849
AN:
1461246
Hom.:
113
Cov.:
32
AF XY:
0.0107
AC XY:
7781
AN XY:
726922
show subpopulations
Gnomad4 AFR exome
AF:
0.00266
Gnomad4 AMR exome
AF:
0.00537
Gnomad4 ASJ exome
AF:
0.0313
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00526
Gnomad4 FIN exome
AF:
0.00649
Gnomad4 NFE exome
AF:
0.0116
Gnomad4 OTH exome
AF:
0.0128
GnomAD4 genome
AF:
0.00814
AC:
1240
AN:
152292
Hom.:
9
Cov.:
33
AF XY:
0.00780
AC XY:
581
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.00193
Gnomad4 AMR
AF:
0.00863
Gnomad4 ASJ
AF:
0.0346
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00663
Gnomad4 FIN
AF:
0.00433
Gnomad4 NFE
AF:
0.0115
Gnomad4 OTH
AF:
0.0142
Alfa
AF:
0.0116
Hom.:
11
Bravo
AF:
0.00851
Asia WGS
AF:
0.00433
AC:
15
AN:
3478
EpiCase
AF:
0.0124
EpiControl
AF:
0.0133

ClinVar

Significance: Benign
Submissions summary: Benign:20Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:8
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 16, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

Mar 20, 2012
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

- -

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

- -

Feb 21, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Gln370Gln in exon 11 of TSC2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 1.5% (125/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs1800742). -

Nov 13, 2013
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Tuberous sclerosis 2 Benign:5
Mar 29, 2019
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
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

- -

Nov 07, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 30, 2017
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:4
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Aug 23, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The c.1110G>A (p.Gln370=) in TSC2 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.01 predominantly in individuals of European descent (0.016; 1083/65734) including 12 homozygous spread through 4 out of 6 populations. The variant of interest has been reported as polymorphism via publications and cited as Benign by multiple reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

Nov 13, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

TSC2: BP4, BP7, BS1, BS2 -

Tuberous sclerosis syndrome Benign:2Other:1
-
Tuberous sclerosis database (TSC2)
Significance: not provided
Review Status: no classification provided
Collection Method: curation

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 05, 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:1
Nov 21, 2014
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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.49
CADD
Benign
7.8
DANN
Benign
0.59
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs1800742; hg19: chr16-2110805; COSMIC: COSV99554856; COSMIC: COSV99554856; API