rs45517202

Variant names:

• chr16-2070535-A-G
• rs45517202
• NM_000548.5:c.1796A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-2070535-A-G
• chr16-2070535-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000548.5(TSC2):​c.1796A>G​(p.Lys599Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. K599M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.95
• Publications: 10 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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 3 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 benign, 34 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31025937).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.1796A>G	p.Lys599Arg	missense	Exon 17 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.1796A>G	p.Lys599Arg	missense	Exon 17 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.1796A>G	p.Lys599Arg	missense	Exon 17 of 41	NP_001107854.1	P49815-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.1796A>G	p.Lys599Arg	missense	Exon 17 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.1796A>G	p.Lys599Arg	missense	Exon 17 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.1796A>G	p.Lys599Arg	missense	Exon 17 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250664 AF XY: 0.00

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

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: 0.00000137 AC: 2 AN: 1460946 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726784

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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: 52494

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	1	Tuberous sclerosis 2 (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.56
Sift	Benign	0.13	T
Sift4G	Uncertain	0.041	D
Polyphen		0.85	P
Vest4		0.42
MutPred		0.52		Loss of ubiquitination at K599 (P = 0.0199)
MVP		0.71
ClinPred		0.078	T
GERP RS		2.1
Varity_R		0.046
gMVP		0.31
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs45517202; hg19: chr16-2120536;