chr16-2072310-A-C

Position:

• chr16-2072310-A-C

Variant summary

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

The NM_000548.5(TSC2):​c.2167A>C​(p.Ile723Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/20 in silico tools predict 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. I723V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.2167A>C	p.Ile723Leu	missense_variant	20/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.2167A>C	p.Ile723Leu	missense_variant	20/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The p.I723L variant (also known as c.2167A>C), located in coding exon 19 of the TSC2 gene, results from an A to C substitution at nucleotide position 2167. The isoleucine at codon 723 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Uncertain	0.54	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.66
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.77	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.34	N;.;.;.;N;N;.;.;.;N;.;N;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.0	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.42
Sift	Benign	0.12	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.41	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.036	B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.44
MutPred		0.81		Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);.;Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);.;Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);.;
MVP		0.88
ClinPred		0.10	T
GERP RS		-1.2
Varity_R		0.12
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr16-2122311;