16-2055493-C-T

Variant names:

• chr16-2055493-C-T
• rs397515059
• NM_000548.5:c.573C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000548.5(TSC2):​c.573C>T​(p.Leu191Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,008 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). Synonymous variant affecting the same amino acid position (i.e. L191L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5 O:1
• Conservation: PhyloP100: -0.301
• Publications: 2 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 16-2055493-C-T is Benign according to our data. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080. Variant chr16-2055493-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 65080.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.573C>T	p.Leu191Leu	synonymous_variant	Exon 6 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.573C>T	p.Leu191Leu	synonymous_variant	Exon 6 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251496 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Benign:3

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome Benign:1 Other:1

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

May 08, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jan 05, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Hereditary cancer-predisposing syndrome Benign:1

May 16, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.12
DANN	Benign	0.42
PhyloP100		-0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: 26

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

Other links and lift over

dbSNP: rs397515059; hg19: chr16-2105494; COSMIC: COSV54763903; COSMIC: COSV54763903;