16-2055493-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_000548.5(TSC2):​c.573C>G​(p.Leu191Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,838 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-2055493-C-G is Benign according to our data. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097. Variant chr16-2055493-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 198097.
• BP7: Synonymous conserved (PhyloP=-0.301 with no splicing effect.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251496 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 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: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 1111968

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Benign:3

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. -

Oct 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jan 21, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome Benign:1

Dec 01, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Apr 25, 2023

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	-0.79
CADD	Benign	0.051
DANN	Benign	0.33
PhyloP100		-0.30

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: rs397515059; hg19: chr16-2105494;