rs144712953

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000548.5(TSC2):​c.336+233T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 655,444 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.010 ( 9 hom., cov: 33)
Exomes 𝑓: 0.011 ( 61 hom. )

Consequence

TSC2
NM_000548.5 intron

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: -0.427
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 -14 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BP6
Variant 16-2053685-T-C is Benign according to our data. Variant chr16-2053685-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 133428.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.01 (1524/152328) while in subpopulation NFE AF= 0.014 (954/68018). AF 95% confidence interval is 0.0133. There are 9 homozygotes in gnomad4. There are 777 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1524 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TSC2NM_000548.5 linkuse as main transcriptc.336+233T>C intron_variant ENST00000219476.9 NP_000539.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TSC2ENST00000219476.9 linkuse as main transcriptc.336+233T>C intron_variant 5 NM_000548.5 ENSP00000219476 P49815-1

Frequencies

GnomAD3 genomes
AF:
0.0100
AC:
1523
AN:
152210
Hom.:
9
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00241
Gnomad AMI
AF:
0.00219
Gnomad AMR
AF:
0.00471
Gnomad ASJ
AF:
0.000865
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.0351
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0140
Gnomad OTH
AF:
0.00525
GnomAD3 exomes
AF:
0.00795
AC:
1023
AN:
128756
Hom.:
11
AF XY:
0.00785
AC XY:
553
AN XY:
70430
show subpopulations
Gnomad AFR exome
AF:
0.00229
Gnomad AMR exome
AF:
0.00526
Gnomad ASJ exome
AF:
0.00321
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00125
Gnomad FIN exome
AF:
0.0320
Gnomad NFE exome
AF:
0.0127
Gnomad OTH exome
AF:
0.0114
GnomAD4 exome
AF:
0.0109
AC:
5459
AN:
503116
Hom.:
61
Cov.:
2
AF XY:
0.0102
AC XY:
2789
AN XY:
272878
show subpopulations
Gnomad4 AFR exome
AF:
0.00295
Gnomad4 AMR exome
AF:
0.00568
Gnomad4 ASJ exome
AF:
0.00299
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00190
Gnomad4 FIN exome
AF:
0.0324
Gnomad4 NFE exome
AF:
0.0133
Gnomad4 OTH exome
AF:
0.0110
GnomAD4 genome
AF:
0.0100
AC:
1524
AN:
152328
Hom.:
9
Cov.:
33
AF XY:
0.0104
AC XY:
777
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.00241
Gnomad4 AMR
AF:
0.00470
Gnomad4 ASJ
AF:
0.000865
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.0351
Gnomad4 NFE
AF:
0.0140
Gnomad4 OTH
AF:
0.00520
Alfa
AF:
0.0110
Hom.:
1
Bravo
AF:
0.00767
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxJun 18, 2018This 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. -
not specified Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.89
CADD
Benign
2.5
DANN
Benign
0.50
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0

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: rs144712953; hg19: chr16-2103686; API