16-2057163-A-T

Variant names:

• chr16-2057163-A-T
• rs397515266
• NM_000548.5:c.833A>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.833A>T​(p.His278Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000214 in 1,399,466 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. H278R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.46
• 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 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 8 benign, 45 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28398246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.833A>T	p.His278Leu	missense_variant	Exon 9 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.833A>T	p.His278Leu	missense_variant	Exon 9 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000128 AC: 2 AN: 156846 AF XY: 0.0000242

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000807

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: 0.00000214 AC: 3 AN: 1399466 Hom.: 0 Cov.: 32 AF XY: 0.00000435 AC XY: 3 AN XY: 690268

African (AFR) AF: 0.00 AC: 0 AN: 31602

American (AMR) AF: 0.0000560 AC: 2 AN: 35718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 35740

South Asian (SAS) AF: 0.00 AC: 0 AN: 79266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1079030

Other (OTH) AF: 0.00 AC: 0 AN: 58020

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Uncertain	0.54	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.0	N;.;.;.;N;N;.;.;.;N;.;N;.;.;.
PhyloP100		5.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.2	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.026	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.041	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.10	B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.51
MutPred		0.49		Loss of disorder (P = 0.1303);Loss of disorder (P = 0.1303);Loss of disorder (P = 0.1303);.;Loss of disorder (P = 0.1303);Loss of disorder (P = 0.1303);Loss of disorder (P = 0.1303);Loss of disorder (P = 0.1303);.;Loss of disorder (P = 0.1303);Loss of disorder (P = 0.1303);Loss of disorder (P = 0.1303);Loss of disorder (P = 0.1303);Loss of disorder (P = 0.1303);.;
MVP		0.86
ClinPred		0.16	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.47
Mutation Taster		=40/60	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: rs397515266; hg19: chr16-2107164;