rs45517141

chr16-2058846-G-Achr16-2058846-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000548.5(TSC2):c.948G>A(p.Pro316=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 1,607,610 control chromosomes in the GnomAD database, including 6 homozygotes. 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. P316P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (3 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: -2.13

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-2058846-G-A is Benign according to our data. Variant chr16-2058846-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 49395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2058846-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00343 (523/152310) while in subpopulation AFR AF= 0.0121 (502/41568). AF 95% confidence interval is 0.0112. There are 3 homozygotes in gnomad4. There are 236 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 524 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.948G>A	p.Pro316=	synonymous_variant	10/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.948G>A	p.Pro316=	synonymous_variant	10/42	5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 524 AN: 152192 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

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: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000849 AC: 203 AN: 239038 Hom.: 0 AF XY: 0.000557 AC XY: 72 AN XY: 129198

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.000599

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000837

Gnomad OTH exome AF: 0.000338

GnomAD4 exome AF: 0.000401 AC: 583 AN: 1455300 Hom.: 3 Cov.: 32 AF XY: 0.000358 AC XY: 259 AN XY: 723158

Gnomad4 AFR exome AF: 0.0118

Gnomad4 AMR exome AF: 0.000570

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.0000236

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000956

Gnomad4 OTH exome AF: 0.000847

GnomAD4 genome AF: 0.00343 AC: 523 AN: 152310 Hom.: 3 Cov.: 33 AF XY: 0.00317 AC XY: 236 AN XY: 74484

Gnomad4 AFR AF: 0.0121

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000822 Hom.: 1

Bravo AF: 0.00402

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Pro316Pro in exon 10 of TSC2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 1.3% (56/4392) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs45517141). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2013	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:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 21, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	TSC2: BP4, BP7, BS1, BS2 -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 01, 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 23, 2020	- -

Tuberous sclerosis syndrome Benign:1 Other:1

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	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.23
Dann	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45517141; hg19: chr16-2108847; COSMIC: COSV104375872; COSMIC: COSV104375872;