rs1060500957

Variant names:

• chr16-2088455-G-A
• rs1060500957
• NM_000548.5:c.5269G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000548.5(TSC2):​c.5269G>A​(p.Glu1757Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,510 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E1757A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 5.74
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 16-2088455-G-A is Benign according to our data. Variant chr16-2088455-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 406083.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.5269G>A	p.Glu1757Lys	missense	Exon 42 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.5266G>A	p.Glu1756Lys	missense	Exon 42 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.5200G>A	p.Glu1734Lys	missense	Exon 41 of 41	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.5269G>A	p.Glu1757Lys	missense	Exon 42 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.5200G>A	p.Glu1734Lys	missense	Exon 41 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.5068G>A	p.Glu1690Lys	missense	Exon 40 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250192 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460510 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726554

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1 Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 31, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tuberous sclerosis syndrome Uncertain:1

Nov 30, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Isolated focal cortical dysplasia type II Uncertain:1

Oct 25, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Uncertain:1

Jul 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1757K variant (also known as c.5269G>A), located in coding exon 41 of the TSC2 gene, results from a G to A substitution at nucleotide position 5269. The glutamic acid at codon 1757 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.026	D
Polyphen		0.99	D
Vest4		0.45
MutPred		0.29		Gain of MoRF binding (P = 0.0117)
MVP		0.90
ClinPred		0.83	D
GERP RS		4.5
Varity_R		0.19
gMVP		0.49
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1060500957; hg19: chr16-2138456; COSMIC: COSV51912980; COSMIC: COSV51912980;