NM_000548.5:c.3815-20C>T

Variant names:

• chr16-2082416-C-T
• rs201878712
• NM_000548.5:c.3815-20C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000548.5(TSC2):​c.3815-20C>T variant causes a intron change. The variant allele was found at a frequency of 0.000254 in 1,612,362 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.46
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 16-2082416-C-T is Benign according to our data. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082416-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000499 (76/152386) while in subpopulation AMR AF = 0.00222 (34/15314). AF 95% confidence interval is 0.00163. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.3815-20C>T		intron_variant	Intron 31 of 41	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.3815-20C>T		intron_variant	Intron 31 of 41	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152268 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000412 AC: 103 AN: 250202 AF XY: 0.000376

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00538

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000228 AC: 333 AN: 1459976 Hom.: 1 Cov.: 31 AF XY: 0.000246 AC XY: 179 AN XY: 726336

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000716 AC: 32 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00704 AC: 184 AN: 26130

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51728

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1111848

Other (OTH) AF: 0.000862 AC: 52 AN: 60346

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152386 Hom.: 0 Cov.: 34 AF XY: 0.000483 AC XY: 36 AN XY: 74516

African (AFR) AF: 0.000120 AC: 5 AN: 41592

American (AMR) AF: 0.00222 AC: 34 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68044

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00137 Hom.: 0

Bravo AF: 0.000842

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 30, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

not specified Benign:2

Sep 25, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.62
PhyloP100		4.5
PromoterAI		0.076	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs201878712; hg19: chr16-2132417;