NM_000548.5:c.2451C>G

Variant names:

• chr16-2074295-C-G
• rs201442542
• NM_000548.5:c.2451C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4 BS2

The NM_000548.5(TSC2):​c.2451C>G​(p.Asp817Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D817N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 34 uncertain in NM_000548.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.3234506).
• BS2: High AC in GnomAdExome4 at 8 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.2451C>G	p.Asp817Glu	missense	Exon 22 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.2451C>G	p.Asp817Glu	missense	Exon 22 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.2451C>G	p.Asp817Glu	missense	Exon 22 of 41	NP_001107854.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.2451C>G	p.Asp817Glu	missense	Exon 22 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.2451C>G	p.Asp817Glu	missense	Exon 22 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.2451C>G	p.Asp817Glu	missense	Exon 22 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460882 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726742

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

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: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.99	L
PhyloP100		1.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.55
Sift	Benign	0.12	T
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.69
MutPred		0.46		Gain of catalytic residue at D817 (P = 0.0662)
MVP		0.91
ClinPred		0.24	T
GERP RS		0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.46
Mutation Taster		=85/15	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: rs201442542; hg19: chr16-2124296;