NM_000548.5:c.1362-10C>A

Variant names:

• chr16-2062962-C-A
• rs45446697
• NM_000548.5:c.1362-10C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000548.5(TSC2):​c.1362-10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Scores: Splicing: ADA: 0.9970
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:3 B:1 O:1
• Conservation: PhyloP100: -0.133

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1362-10C>A		intron_variant	Intron 13 of 41	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1362-10C>A		intron_variant	Intron 13 of 41	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1397076 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000643 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:3 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Feb 05, 2024

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Some individuals were reported to have a variable and/or mild presentation (PMID: 10735580, 17304050, 26540169, internal patient(s), and personal communication related to ClinVar ID: 50185, Accession: SCV000644236.7). This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) Computational tools yielded predictions that this variant may interfere with normal RNA splicing. RT-PCR analysis was unable to confirm an effect on RNA splicing, however it is uncertain whether the detection method used would identify a small, in-frame length change of this exon (PMID: 26540169). -

Mar 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TSC2 c.1362-10C>A variant (rs45446697) has been observed in several individuals and families with TSC2-related disease (Choy 1999, Tyburczy 2015, ARUP internal data, personal communication). This variant is also reported in ClinVar (Variation ID: 50185). It is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This is an intronic variant and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site. Based on available information, this variant is considered to be likely pathogenic. References: Choy YS et al. Superiority of denaturing high performance liquid chromatography over single-stranded conformation and conformation-sensitive gel electrophoresis for mutation detection in TSC2. Ann Hum Genet. 1999 Sep;63(Pt 5):383-91. PMID: 10735580. Tyburczy ME et al. Mosaic and Intronic Mutations in TSC1/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing. PLoS Genet. 2015 Nov 5;11(11):e1005637. PMID: 26540169. -

Mar 01, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as a benign variant in published literature; however, additional information was not provided (PMID: 17304050); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS12-10C>A; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 10735580, 26540169, 17304050) -

Tuberous sclerosis 2 Pathogenic:1 Uncertain:1 Benign:1

Nov 30, 2021

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes: PM2, PP3 -

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 13 of the TSC2 gene. It does not directly change the encoded amino acid sequence of the TSC2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with tuberous sclerosis complex (PMID: 26540169; internal data). ClinVar contains an entry for this variant (Variation ID: 50185). Studies have shown that this variant is associated with inconclusive levels of altered splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: flagged submission

Collection Method: clinical testing

- -

Isolated focal cortical dysplasia type II Pathogenic:1

Jun 03, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 05, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1362-10C>A intronic pathogenic mutation results from a C to A substitution 10 nucleotides upstream from coding exon 13 in the TSC2 gene. This alteration has been observed in many individuals with a personal and/or family history that is consistent with TSC2-related disease (Ambry internal data; Personal communication; Tyburczy ME et al. PLoS Genet, 2015 Nov;11:e1005637; Choy YS et al. Ann Hum Genet, 1999 Sep;63:383-91). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

TSC2-related disorder Uncertain:1

May 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TSC2 c.1362-10C>A variant is predicted to interfere with splicing. The c.1362-10 C>A intronic variant in the TSC2 gene has been reported in individuals affected with tuberous sclerosis, and has been reported to segregate with affected status within a family; however, minimal details were provided (Tyburczy et al. 2015. PubMed ID: 26540169; Choy et al. 1999. PubMed ID: 10735580; Au et al. 2007. PubMed ID: 17304050; https://databases.lovd.nl/shared/variants/TSC2). This variant is predicted to abolish the canonical splice acceptor site based on available splicing prediction programs (Alamut Visual Plus v1.6.1). However, the use of computer prediction programs is not equivalent to functional evidence. In ClinVar this variant has conflicting classifications including pathogenic, likely pathogenic, uncertain significance, and benign (https://preview.ncbi.nlm.nih.gov/clinvar/variation/50185/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Tuberous sclerosis syndrome Other:1

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.10
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.57		Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs45446697; hg19: chr16-2112963;