rs781713438

Positions:

• chr16-2074389-A-G
• chr16-2074389-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM5 BP6 BS2

The NM_000548.5(TSC2):​c.2545A>G​(p.Thr849Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,610,086 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. T849I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense, splice_region
• Scores: Splicing: ADA: 0.6405
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 7.24

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 16 uncertain in NM_000548.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2074389-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2068302.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP6: Variant 16-2074389-A-G is Benign according to our data. Variant chr16-2074389-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 391969.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=1, Likely_benign=1}. Variant chr16-2074389-A-G is described in Lovd as [Benign]. Variant chr16-2074389-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.2545A>G	p.Thr849Ala	missense_variant, splice_region_variant	22/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.2545A>G	p.Thr849Ala	missense_variant, splice_region_variant	22/42	5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 247478 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134382

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00000890

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1457778 Hom.: 0 Cov.: 31 AF XY: 0.00000965 AC XY: 7 AN XY: 725304

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74464

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000189

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Tuberous sclerosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 28, 2023

This missense variant replaces threonine with alanine at codon 849 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has been identified in 3/247478 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2023

The p.T849A variant (also known as c.2545A>G), located in coding exon 21 of the TSC2 gene, results from an A to G substitution at nucleotide position 2545. The threonine at codon 849 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	2.0	M;.;.;.;M;M;.;.;.;M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.3	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.74
Sift	Benign	0.14	T;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.050	T;.;.;T;.;T;.;.;T;T;.;.;.;.;D
Polyphen		0.99	D;.;.;.;D;D;.;.;P;B;.;.;.;.;.
Vest4		0.72
MutPred		0.60		Loss of catalytic residue at T849 (P = 0.0771);Loss of catalytic residue at T849 (P = 0.0771);Loss of catalytic residue at T849 (P = 0.0771);.;Loss of catalytic residue at T849 (P = 0.0771);Loss of catalytic residue at T849 (P = 0.0771);Loss of catalytic residue at T849 (P = 0.0771);Loss of catalytic residue at T849 (P = 0.0771);.;Loss of catalytic residue at T849 (P = 0.0771);Loss of catalytic residue at T849 (P = 0.0771);Loss of catalytic residue at T849 (P = 0.0771);Loss of catalytic residue at T849 (P = 0.0771);Loss of catalytic residue at T849 (P = 0.0771);.;
MVP		0.86
ClinPred		0.80	D
GERP RS		5.4
Varity_R		0.38
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.64
dbscSNV1_RF	Benign	0.41
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: rs781713438; hg19: chr16-2124390;