rs137854074

Variant names:

• chr16-2079667-C-A
• rs137854074
• NM_000548.5:c.3395C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2079667-C-A
• chr16-2079667-C-G
• chr16-2079667-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000548.5(TSC2):​c.3395C>A​(p.Ser1132*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S1132S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC2 NM_000548.5 stop_gained, splice_region
• Scores: Splicing: ADA: 0.7404
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 7.22
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2079667-C-A is Pathogenic according to our data. Variant chr16-2079667-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 49828.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.3395C>A	p.Ser1132*	stop_gained, splice_region_variant	Exon 29 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.3395C>A	p.Ser1132*	stop_gained, splice_region_variant	Exon 29 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: 1435474 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 711850

African (AFR) AF: 0.00 AC: 0 AN: 33058

American (AMR) AF: 0.00 AC: 0 AN: 41076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25614

East Asian (EAS) AF: 0.00 AC: 0 AN: 38604

South Asian (SAS) AF: 0.00 AC: 0 AN: 82876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4646

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100340

Other (OTH) AF: 0.00 AC: 0 AN: 59246

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Nov 21, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The S1132X nonsense variant in the TSC2 gene has been reported previously in association with tuberous sclerosis complex (TSC2 LOVD). The S1132X variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, the presence of S1132X is consistent with a diagnosis of tuberous sclerosis complex -

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_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	62
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.2
Vest4		0.95
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.74
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.28		Position offset: 2

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

Other links and lift over

dbSNP: rs137854074; hg19: chr16-2129668;