chr16-2077619-C-T

Variant names:

• chr16-2077619-C-T
• rs397514968
• NM_000548.5:c.2859C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_000548.5(TSC2):​c.2859C>T​(p.Pro953Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,068 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. P953P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • 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:6 O:1
• Conservation: PhyloP100: 1.99
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 16-2077619-C-T is Benign according to our data. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958. Variant chr16-2077619-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64958.
• BP7: Synonymous conserved (PhyloP=1.99 with no splicing effect.
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.2859C>T	p.Pro953Pro	synonymous_variant	Exon 26 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.2859C>T	p.Pro953Pro	synonymous_variant	Exon 26 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460884 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726748

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74342

African (AFR) AF: 0.0000724 AC: 3 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000293 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Benign:3

Aug 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 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. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

Sep 15, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge -

Jul 01, 2018

CeGaT Center for Human Genetics Tuebingen

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

- -

Sep 09, 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

Nov 13, 2017

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	-0.40
CADD	Benign	14
DANN	Benign	0.72
PhyloP100		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs397514968; hg19: chr16-2127620;