16-2062571-C-T

Variant names:

• chr16-2062571-C-T
• rs535984356
• NM_000548.5:c.1332C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000548.5(TSC2):​c.1332C>T​(p.Asn444Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,611,354 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (3 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.718
• Publications: 4 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 16-2062571-C-T is Benign according to our data. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062571-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.718 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000722 (11/152366) while in subpopulation SAS AF = 0.00186 (9/4832). AF 95% confidence interval is 0.000971. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1332C>T	p.Asn444Asn	synonymous_variant	Exon 13 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1332C>T	p.Asn444Asn	synonymous_variant	Exon 13 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000342 AC: 84 AN: 245468 AF XY: 0.000467

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000585

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000175 AC: 255 AN: 1458988 Hom.: 3 Cov.: 31 AF XY: 0.000236 AC XY: 171 AN XY: 725380

African (AFR) AF: 0.0000299 AC: 1 AN: 33442

American (AMR) AF: 0.0000674 AC: 3 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00254 AC: 217 AN: 85500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53174

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5722

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1110666

Other (OTH) AF: 0.000282 AC: 17 AN: 60278

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.0000939 AC XY: 7 AN XY: 74508

African (AFR) AF: 0.00 AC: 0 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4832

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000302

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Benign:4

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 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. -

not provided Benign:2

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TSC2: BP4, BP7, BS1 -

Jul 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Dec 13, 2015

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. -

Feb 17, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome Benign:1

Nov 30, 2023

All of Us Research Program, National Institutes of Health

Significance: 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	-0.34
CADD	Benign	7.9
DANN	Benign	0.71
PhyloP100		0.72
PromoterAI		-0.020	Neutral
Mutation Taster		=98/2	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: rs535984356; hg19: chr16-2112572;