rs149543046

Positions:

• chr16-2070560-G-A
• chr16-2070560-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000548.5(TSC2):​c.1821G>A​(p.Ala607Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,613,032 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.334

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 16-2070560-G-A is Benign according to our data. Variant chr16-2070560-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 65382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070560-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.334 with no splicing effect.
• BS2: High AC in GnomAd4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1821G>A	p.Ala607Ala	synonymous_variant	17/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1821G>A	p.Ala607Ala	synonymous_variant	17/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000296 AC: 74 AN: 250376 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135766

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.000897

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000399

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000372 AC: 544 AN: 1460802 Hom.: 0 Cov.: 34 AF XY: 0.000361 AC XY: 262 AN XY: 726708

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000573

Gnomad4 NFE exome AF: 0.000407

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74380

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000343 Hom.: 0

Bravo AF: 0.000601

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis syndrome Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2014	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. -

Tuberous sclerosis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 22, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 08, 2015	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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2024

TSC2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.1
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs149543046; hg19: chr16-2120561;