rs13335638

Variant names:

• chr16-2086623-T-C
• rs13335638
• NM_000548.5:c.4850-109T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-2086623-T-C
• chr16-2086623-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000548.5(TSC2):​c.4850-109T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,538,084 control chromosomes in the GnomAD database, including 33,023 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (8001 hom., cov: 33)
  • Exomes 𝑓: 0.18 (25022 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -3.40
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-2086623-T-C is Benign according to our data. Variant chr16-2086623-T-C is described in ClinVar as Benign. ClinVar VariationId is 65253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4850-109T>C		intron_variant	Intron 37 of 41	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4850-109T>C		intron_variant	Intron 37 of 41	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41725 AN: 151976 Hom.: 7964 Cov.: 33

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0928

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.249

GnomAD4 exome AF: 0.177 AC: 244845 AN: 1385990 Hom.: 25022 AF XY: 0.173 AC XY: 118993 AN XY: 686782

African (AFR) AF: 0.550 AC: 17408 AN: 31676

American (AMR) AF: 0.130 AC: 5094 AN: 39232

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 5935 AN: 24502

East Asian (EAS) AF: 0.000241 AC: 9 AN: 37386

South Asian (SAS) AF: 0.0962 AC: 7763 AN: 80720

European-Finnish (FIN) AF: 0.223 AC: 8067 AN: 36172

Middle Eastern (MID) AF: 0.234 AC: 934 AN: 3998

European-Non Finnish (NFE) AF: 0.176 AC: 188646 AN: 1074668

Other (OTH) AF: 0.191 AC: 10989 AN: 57636

GnomAD4 genome AF: 0.275 AC: 41810 AN: 152094 Hom.: 8001 Cov.: 33 AF XY: 0.272 AC XY: 20214 AN XY: 74354

African (AFR) AF: 0.541 AC: 22429 AN: 41470

American (AMR) AF: 0.198 AC: 3024 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 833 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5170

South Asian (SAS) AF: 0.0925 AC: 446 AN: 4822

European-Finnish (FIN) AF: 0.232 AC: 2457 AN: 10586

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11928 AN: 67970

Other (OTH) AF: 0.247 AC: 520 AN: 2108

Alfa AF: 0.157 Hom.: 478

Bravo AF: 0.284

Asia WGS AF: 0.0830 AC: 291 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 21. Only high quality variants are reported. -

not provided Benign:1

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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	-0.92
CADD	Benign	0.82
DANN	Benign	0.43
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs13335638; hg19: chr16-2136624;