NM_000548.5:c.2859C>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_000548.5(TSC2):​c.2859C>G​(p.Pro953Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,884 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. P953P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 16-2077619-C-G is Benign according to our data. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2077619-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 2626448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.99 with no splicing effect.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726748

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 8.99e-7 AC: 1 AN: 1111984

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis syndrome Benign:1

Aug 13, 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 2 Benign:1

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. -

Hereditary cancer-predisposing syndrome Benign:1

Aug 30, 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	-0.47
CADD	Benign	12
DANN	Benign	0.69
PhyloP100		2.0

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: rs397514968; hg19: chr16-2127620;