rs878854095

Variant names:

• chr16-2081743-G-A
• rs878854095
• NM_000548.5:c.3759G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2081743-G-A
• chr16-2081743-G-C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000548.5(TSC2):​c.3759G>A​(p.Leu1253Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,550 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1253L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.748
• Publications: 1 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 -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 16-2081743-G-A is Benign according to our data. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2081743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 1097070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.748 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.3759G>A	p.Leu1253Leu	synonymous_variant	Exon 31 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.3759G>A	p.Leu1253Leu	synonymous_variant	Exon 31 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000801 AC: 2 AN: 249658 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000342 AC: 5 AN: 1460550 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726582

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 34

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Benign:2

Sep 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 30, 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. -

not provided Benign:1

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TSC2: BP4, BP7 -

Hereditary cancer-predisposing syndrome Benign:1

Sep 01, 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	-0.60
CADD	Benign	1.7
DANN	Benign	0.40
PhyloP100		0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs878854095; hg19: chr16-2131744; COSMIC: COSV54764856; COSMIC: COSV54764856;