chr16-2084303-C-G

Variant names:

• chr16-2084303-C-G
• rs560831385
• NM_000548.5:c.4081C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000219476.9(TSC2):​c.4081C>G​(p.Arg1361Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,366 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. R1361Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSC2 ENST00000219476.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.995
• Publications: 3 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24370342).

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.4081C>G	p.Arg1361Gly	missense	Exon 34 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.4078C>G	p.Arg1360Gly	missense	Exon 34 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.4012C>G	p.Arg1338Gly	missense	Exon 33 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.4081C>G	p.Arg1361Gly	missense	Exon 34 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.4012C>G	p.Arg1338Gly	missense	Exon 33 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.3880C>G	p.Arg1294Gly	missense	Exon 32 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460366 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726446

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

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: 8.99e-7 AC: 1 AN: 1111914

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.75	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.99
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.016	D
Sift4G	Benign	0.30	T
Polyphen		0.99	D
Vest4		0.64
MutPred		0.34		Gain of catalytic residue at V1362 (P = 0.0258)
MVP		0.90
ClinPred		0.18	T
GERP RS		1.3
Varity_R		0.12
gMVP		0.33
Mutation Taster		=92/8	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: rs560831385; hg19: chr16-2134304;