rs150397923

chr16-2084538-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000548.5(TSC2):c.4316G>A(p.Gly1439Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000834 in 1,609,116 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1439A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (9 hom., cov: 34)
  • Exomes 𝑓: 0.00047 (6 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:2
• Conservation: PhyloP100: 2.90

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051838458).
• BP6: Variant 16-2084538-G-A is Benign according to our data. Variant chr16-2084538-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 65126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084538-G-A is described in Lovd as [Benign]. Variant chr16-2084538-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00432 (659/152372) while in subpopulation AFR AF= 0.0151 (630/41588). AF 95% confidence interval is 0.0142. There are 9 homozygotes in gnomad4. There are 303 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 659 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.4316G>A	p.Gly1439Asp	missense_variant	34/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.4316G>A	p.Gly1439Asp	missense_variant	34/42	5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.00433 AC: 659 AN: 152254 Hom.: 9 Cov.: 34

Gnomad AFR AF: 0.0152

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: 0.00525

GnomAD3 exomes AF: 0.00116 AC: 275 AN: 238078 Hom.: 4 AF XY: 0.000811 AC XY: 106 AN XY: 130636

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.000707

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000469 AC: 683 AN: 1456744 Hom.: 6 Cov.: 33 AF XY: 0.000379 AC XY: 275 AN XY: 724764

Gnomad4 AFR exome AF: 0.0178

Gnomad4 AMR exome AF: 0.000787

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000763

GnomAD4 genome AF: 0.00432 AC: 659 AN: 152372 Hom.: 9 Cov.: 34 AF XY: 0.00407 AC XY: 303 AN XY: 74506

Gnomad4 AFR AF: 0.0151

Gnomad4 AMR AF: 0.000914

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: 0.00520

Alfa AF: 0.000695 Hom.: 2

Bravo AF: 0.00484

ESP6500AA AF: 0.0129 AC: 56

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00143 AC: 172

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 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. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 27, 2021	- -

Tuberous sclerosis 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Tuberous sclerosis syndrome Benign:2 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	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 12, 2018	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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Aug 19, 2015

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2014

This alteration is classified as 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
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	16
Dann	Benign	0.58
DEOGEN2	Uncertain	0.51	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.78
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0052	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.53
Sift	Benign	0.63	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.21	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.18	B;.;.;.;P;P;.;.;P;P;.;.;.;.;.
Vest4		0.30
MVP		0.95
ClinPred		0.018	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.054
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150397923; hg19: chr16-2134539; COSMIC: COSV104375892; COSMIC: COSV104375892;