chr16-2083702-C-T

Variant names:

• chr16-2083702-C-T
• rs373508609
• NM_000548.5:c.3891C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000548.5(TSC2):​c.3891C>T​(p.Ala1297Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,585,690 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. A1297A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.38
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 16-2083702-C-T is Benign according to our data. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2083702-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 413730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.38 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.3891C>T	p.Ala1297Ala	synonymous_variant	Exon 33 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.3891C>T	p.Ala1297Ala	synonymous_variant	Exon 33 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000293 AC: 6 AN: 204718 AF XY: 0.0000364

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000643

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000222

Gnomad OTH exome AF: 0.000191

GnomAD4 exome AF: 0.0000140 AC: 20 AN: 1433496 Hom.: 0 Cov.: 32 AF XY: 0.0000127 AC XY: 9 AN XY: 710172

African (AFR) AF: 0.00 AC: 0 AN: 33252

American (AMR) AF: 0.00 AC: 0 AN: 39580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25464

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38756

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82166

European-Finnish (FIN) AF: 0.0000199 AC: 1 AN: 50188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.0000127 AC: 14 AN: 1098948

Other (OTH) AF: 0.0000505 AC: 3 AN: 59412

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 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. -

Tuberous sclerosis syndrome Benign:1

Nov 30, 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 Benign:1

Aug 06, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Mar 29, 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	-0.76
CADD	Benign	0.030
DANN	Benign	0.44
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs373508609; hg19: chr16-2133703;