rs944693159

Positions:

• chr16-2082472-A-C
• chr16-2082472-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000548.5(TSC2):​c.3851A>C​(p.Gln1284Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.36

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17674288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.3851A>C	p.Gln1284Pro	missense_variant	32/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.3851A>C	p.Gln1284Pro	missense_variant	32/42	5	NM_000548.5	ENSP00000219476

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Benign	0.79
DEOGEN2	Uncertain	0.46	T;.;.;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.095
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.78	T;T;T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.9	M;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.59	N;.;.;.;.
REVEL	Uncertain	0.45
Sift	Benign	0.096	T;.;.;.;.
Sift4G	Benign	0.24	T;.;.;.;.
Polyphen		0.0030	B;B;.;.;.
Vest4		0.56
MVP		0.92
ClinPred		0.25	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs944693159; hg19: chr16-2132473;