rs1555506852

Variant names:

• chr16-2072855-G-A
• rs1555506852
• NM_000548.5:c.2227G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The ENST00000219476.9(TSC2):​c.2227G>A​(p.Gly743Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,274 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G743D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSC2 ENST00000219476.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.98
• 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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 31 uncertain in ENST00000219476.9
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22369462).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000219476.9. 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.2227G>A	p.Gly743Ser	missense	Exon 21 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.2227G>A	p.Gly743Ser	missense	Exon 21 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.2227G>A	p.Gly743Ser	missense	Exon 21 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.2227G>A	p.Gly743Ser	missense	Exon 21 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.2227G>A	p.Gly743Ser	missense	Exon 21 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.2227G>A	p.Gly743Ser	missense	Exon 21 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461274 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726924

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

American (AMR) AF: 0.00 AC: 0 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: 52826

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Tuberous sclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.15
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	-0.69	N
PhyloP100		6.0
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.34	N
REVEL	Uncertain	0.35
Sift	Benign	0.12	T
Sift4G	Benign	0.15	T
Polyphen		0.0010	B
Vest4		0.32
MutPred		0.42		Gain of disorder (P = 0.0435)
MVP		0.64
ClinPred		0.86	D
GERP RS		4.5
Varity_R		0.081
gMVP		0.28
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1555506852; hg19: chr16-2122856;