rs200929621

chr16-2074248-A-Gchr16-2074248-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM1 BP4_Moderate BP6 BS1 BS2

The NM_000548.5(TSC2):c.2404A>G(p.Ser802Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000986 in 1,612,754 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S802N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 4.45

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 -9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 13 uncertain in NM_000548.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.10086098).
• BP6: Variant 16-2074248-A-G is Benign according to our data. Variant chr16-2074248-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 406060.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=3}. Variant chr16-2074248-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000105 (153/1460412) while in subpopulation EAS AF= 0.00378 (150/39700). AF 95% confidence interval is 0.00328. There are 1 homozygotes in gnomad4_exome. There are 79 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.2404A>G	p.Ser802Gly	missense_variant	22/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.2404A>G	p.Ser802Gly	missense_variant	22/42	5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152224 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: 0.00115

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000400 AC: 10 AN: 250296 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135652

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000544

Gnomad SAS 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: 0.000105 AC: 153 AN: 1460412 Hom.: 1 Cov.: 31 AF XY: 0.000109 AC XY: 79 AN XY: 726522

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00378

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 18, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 07, 2019	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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Apr 25, 2017

- -

Tuberous sclerosis syndrome Benign: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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

TSC2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.034
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.28	T
MutationAssessor	Benign	1.5	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.35
Sift	Benign	0.051	T;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Benign	0.21	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.16	B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.33
MutPred		0.50		Loss of catalytic residue at S802 (P = 0.067);Loss of catalytic residue at S802 (P = 0.067);Loss of catalytic residue at S802 (P = 0.067);.;Loss of catalytic residue at S802 (P = 0.067);Loss of catalytic residue at S802 (P = 0.067);Loss of catalytic residue at S802 (P = 0.067);Loss of catalytic residue at S802 (P = 0.067);.;Loss of catalytic residue at S802 (P = 0.067);Loss of catalytic residue at S802 (P = 0.067);Loss of catalytic residue at S802 (P = 0.067);Loss of catalytic residue at S802 (P = 0.067);Loss of catalytic residue at S802 (P = 0.067);.;
MVP		0.77
ClinPred		0.083	T
GERP RS		4.2
Varity_R		0.15
gMVP		0.31

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: rs200929621; hg19: chr16-2124249;