rs1555516036

Variant names:

• chr16-2086233-C-G
• rs1555516036
• NM_000548.5:c.4703C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-2086233-C-G
• chr16-2086233-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 6P and 4B. PM1 PP3_Strong BS2

The NM_000548.5(TSC2):​c.4703C>G​(p.Ser1568Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,460,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1568P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.11
• Publications: 0 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 2 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 36 uncertain in NM_000548.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• BS2: High AC in GnomAdExome4 at 17 AD gene.

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.4703C>G	p.Ser1568Cys	missense	Exon 37 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.4700C>G	p.Ser1567Cys	missense	Exon 37 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.4634C>G	p.Ser1545Cys	missense	Exon 36 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.4703C>G	p.Ser1568Cys	missense	Exon 37 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.4634C>G	p.Ser1545Cys	missense	Exon 36 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.4502C>G	p.Ser1501Cys	missense	Exon 35 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1460492 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 726546

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

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52122

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

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111952

Other (OTH) AF: 0.0000166 AC: 1 AN: 60370

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Tuberous sclerosis 2 (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Isolated focal cortical dysplasia type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.94
Sift	Benign	0.10	T
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.79		Loss of disorder (P = 0.0063)
MVP		0.92
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.82
gMVP		0.93
Mutation Taster		=15/85	disease causing

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: rs1555516036; hg19: chr16-2136234;