16-2050409-A-T

Position:

• chr16-2050409-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000548.5(TSC2):​c.148A>T​(p.Met50Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M50V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.744

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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 5 benign, 15 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07648942).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.148A>T	p.Met50Leu	missense_variant	3/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.148A>T	p.Met50Leu	missense_variant	3/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461658 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.64
DEOGEN2	Benign	0.40	T;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.72	T;T;T;D;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.028	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	N;.;.;.;N;N;.;.;N;N;.;.;N;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.70	N;.;.;N;.;N;.;.;N;N;.;.;.;.;.;N
REVEL	Benign	0.14
Sift	Benign	0.43	T;.;.;T;.;T;.;.;T;T;.;.;.;.;.;T
Sift4G	Benign	0.88	T;.;.;T;.;T;.;.;T;T;.;.;.;.;.;T
Polyphen		0.0	B;.;.;.;.;B;.;.;B;B;.;.;.;.;.;.
Vest4		0.20
MutPred		0.54		Loss of catalytic residue at M50 (P = 5e-04);Loss of catalytic residue at M50 (P = 5e-04);Loss of catalytic residue at M50 (P = 5e-04);.;Loss of catalytic residue at M50 (P = 5e-04);Loss of catalytic residue at M50 (P = 5e-04);Loss of catalytic residue at M50 (P = 5e-04);Loss of catalytic residue at M50 (P = 5e-04);Loss of catalytic residue at M50 (P = 5e-04);Loss of catalytic residue at M50 (P = 5e-04);Loss of catalytic residue at M50 (P = 5e-04);Loss of catalytic residue at M50 (P = 5e-04);Loss of catalytic residue at M50 (P = 5e-04);Loss of catalytic residue at M50 (P = 5e-04);Loss of catalytic residue at M50 (P = 5e-04);.;
MVP		0.28
ClinPred		0.025	T
GERP RS		2.6
Varity_R		0.032
gMVP		0.097

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2100410;