rs45446697

Positions:

• chr16-2062962-C-A
• chr16-2062962-C-G
• chr16-2062962-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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:4 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1362-10C>A		intron_variant		ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1362-10C>A		intron_variant		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:4 Uncertain:3 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Nov 30, 2021	ACMG codes: PM2, PP3 -
Benign, flagged submission	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	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; Invitae). ClinVar contains an entry for this variant (Variation ID: 50185). Studies have shown that this variant is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2024	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 05, 2024	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). -

Isolated focal cortical dysplasia type II Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 03, 2024

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2023

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

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

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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;