NM_000548.5:c.5097G>C

Variant names:

• chr16-2088076-G-C
• rs397515314
• NM_000548.5:c.5097G>C

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.5097G>C​(p.Val1699Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,612,676 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. V1699V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (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 O:1
• Conservation: PhyloP100: 1.11
• 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=-0.61).
• BP6: Variant 16-2088076-G-C is Benign according to our data. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088076-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 65147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.11 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.5097G>C	p.Val1699Val	synonymous_variant	Exon 40 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.5097G>C	p.Val1699Val	synonymous_variant	Exon 40 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000439 AC: 11 AN: 250416 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1460510 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 726584

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.000335 AC: 15 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52130

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111982

Other (OTH) AF: 0.0000331 AC: 2 AN: 60382

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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

- -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 06, 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 Other:1

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

not specified Benign:1

Aug 26, 2022

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Jan 14, 2016

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	-0.61
CADD	Benign	6.9
DANN	Benign	0.60
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397515314; hg19: chr16-2138077;