16-2055505-C-T

Variant names:

• chr16-2055505-C-T
• rs397515309
• NM_000548.5:c.585C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000548.5(TSC2):​c.585C>T​(p.Ile195Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,690 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. I195I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.209
• Publications: 2 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 -12 ACMG points.

• BP6: Variant 16-2055505-C-T is Benign according to our data. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055505-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 536097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.585C>T	p.Ile195Ile	synonymous_variant	Exon 6 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.585C>T	p.Ile195Ile	synonymous_variant	Exon 6 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152170 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000965

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251492 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000615

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461520 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 727118

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

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

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

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

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

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

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111680

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152170 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74342

African (AFR) AF: 0.0000965 AC: 4 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000354 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Benign:2

May 08, 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. -

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome Benign:1

Dec 13, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Benign:1

Oct 04, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Feb 27, 2020

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	-0.44
CADD	Benign	2.7
DANN	Benign	0.72
PhyloP100		-0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.35		Position offset: 14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397515309; hg19: chr16-2105506; COSMIC: COSV99552726; COSMIC: COSV99552726;