NM_000548.5:c.4610T>C

Variant names:

• chr16-2085270-T-C
• rs760056622
• NM_000548.5:c.4610T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 3P and 16B. PM1 PP3 BP6_Very_Strong BS1 BS2

The NM_000548.5(TSC2):​c.4610T>C​(p.Ile1537Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000288 in 1,460,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. I1537N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.07
• Publications: 3 publications found

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: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 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, 31 uncertain in NM_000548.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758
• BP6: Variant 16-2085270-T-C is Benign according to our data. Variant chr16-2085270-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 579053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000288 (42/1460420) while in subpopulation SAS AF = 0.000441 (38/86258). AF 95% confidence interval is 0.00033. There are 0 homozygotes in GnomAdExome4. There are 36 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4610T>C	p.Ile1537Thr	missense_variant	Exon 36 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4610T>C	p.Ile1537Thr	missense_variant	Exon 36 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000480 AC: 12 AN: 250020 AF XY: 0.0000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000288 AC: 42 AN: 1460420 Hom.: 0 Cov.: 33 AF XY: 0.0000496 AC XY: 36 AN XY: 726516

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000441 AC: 38 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111918

Other (OTH) AF: 0.0000497 AC: 3 AN: 60370

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000742 AC: 9

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Benign:2

Aug 23, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TSC2: PP3, BS1, BS2 -

Hereditary cancer-predisposing syndrome Benign:1

Mar 03, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		5.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.9	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.014	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.99	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.67
MutPred		0.42		Loss of stability (P = 0.0148);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.60
ClinPred		0.71	D
GERP RS		4.5
Varity_R		0.62
gMVP		0.55
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs760056622; hg19: chr16-2135271;