16-2086841-C-A

Variant names:

• chr16-2086841-C-A
• rs45517384
• NM_000548.5:c.4959C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000548.5(TSC2):​c.4959C>A​(p.Ser1653Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S1653S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: -2.92
• Publications: 12 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: 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.4959C>A	p.Ser1653Ser	synonymous_variant	Exon 38 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4959C>A	p.Ser1653Ser	synonymous_variant	Exon 38 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451540 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721422

African (AFR) AF: 0.00 AC: 0 AN: 33222

American (AMR) AF: 0.00 AC: 0 AN: 43694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39162

South Asian (SAS) AF: 0.00 AC: 0 AN: 84988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5150

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108002

Other (OTH) AF: 0.00 AC: 0 AN: 59936

GnomAD4 genome Cov.: 33

Alfa AF: 0.00425 Hom.: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Feb 11, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TSC2 c.4959C>A alters a non-conserved nucleotide resulting in a synonymous change in exon 38. Several computational tools predict a conflicting impact on normal splicing: Two predict the variant strengthens a cryptic exonic 3' splicing acceptor site. One predicts the variant strengthens a cryptic exonic 5' splicing donor site. One predicts no significant impact on splicing at the canonical intron 38 splicing donor site. Lastly, Transcript Inferred Pathogenicity (TraP) predicts a benign impact. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 232198 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4959C>A in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 49462). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Tuberous sclerosis 2 Uncertain:1

Nov 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 49462). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 1653 of the TSC2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TSC2 protein. -

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	-0.75
CADD	Benign	6.4
DANN	Benign	0.73
PhyloP100		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.79		Position offset: 1

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

Other links and lift over

dbSNP: rs45517384; hg19: chr16-2136842; COSMIC: COSV51924493; COSMIC: COSV51924493;