rs45505895

chr16-2080188-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000548.5(TSC2):c.3421G>A(p.Ala1141Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,612,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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. A1141V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:9 O:1
• Conservation: PhyloP100: 1.27

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2080189-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.008429408).
• BP6: Variant 16-2080188-G-A is Benign according to our data. Variant chr16-2080188-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 49258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2080188-G-A is described in Lovd as [Likely_benign]. Variant chr16-2080188-G-A is described in Lovd as [Pathogenic]. Variant chr16-2080188-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000171 (26/152350) while in subpopulation EAS AF= 0.00386 (20/5180). AF 95% confidence interval is 0.00256. There are 1 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.3421G>A	p.Ala1141Thr	missense_variant	30/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.3421G>A	p.Ala1141Thr	missense_variant	30/42	5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152232 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000483 AC: 121 AN: 250320 Hom.: 0 AF XY: 0.000464 AC XY: 63 AN XY: 135672

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00572

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000975

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000119 AC: 174 AN: 1460586 Hom.: 0 Cov.: 32 AF XY: 0.000117 AC XY: 85 AN XY: 726586

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00229

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000674

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74508

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000167 Hom.: 0

Bravo AF: 0.000253

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000478 AC: 58

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1 Benign:1 Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Tuberous sclerosis 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2021	This variant is associated with the following publications: (PMID: 24055113, 25637381, 16981987, 25724664, 32211034) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	TSC2: BP4 -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 26, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 22, 2018	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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 12, 2015

p.Ala1141Thr in exon 30 of TSC2: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, five mammals (squirrel monkey, pig, ferret, hedgehog,and tasmanian devil) have a threonine (T) at this position. Additionally, it has been identified in 0 .6% (50/8590) of East Asian chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org, dbSNP rs45505895). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	14
Dann	Benign	0.34
DEOGEN2	Benign	0.35	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.85	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.0084	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.81	L;.;.;.;.;.;.;.;.;L;.;.;.;.;.
MutationTaster	Benign	0.95	N;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.15	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.54
Sift	Benign	0.46	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.51	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.57	P;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.38
MVP		0.97
ClinPred		0.028	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.017
gMVP		0.26

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

Other links and lift over

dbSNP: rs45505895; hg19: chr16-2130189; COSMIC: COSV99052855; COSMIC: COSV99052855;