chr16-2065544-C-G

Position:

• chr16-2065544-C-G

Variant summary

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

The NM_000548.5(TSC2):​c.1625C>G​(p.Pro542Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P542A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.31

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.

• 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.1625C>G	p.Pro542Arg	missense_variant	16/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1625C>G	p.Pro542Arg	missense_variant	16/42	5	NM_000548.5	ENSP00000219476

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 24, 2016

This sequence change replaces proline with arginine at codon 542 of the TSC2 protein (p.Pro542Arg). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TSC2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.2	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.6	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.013	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Benign	0.13	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		1.0	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.64
MutPred		0.27		Loss of glycosylation at P542 (P = 0.0061);Loss of glycosylation at P542 (P = 0.0061);Loss of glycosylation at P542 (P = 0.0061);.;Loss of glycosylation at P542 (P = 0.0061);Loss of glycosylation at P542 (P = 0.0061);Loss of glycosylation at P542 (P = 0.0061);Loss of glycosylation at P542 (P = 0.0061);.;Loss of glycosylation at P542 (P = 0.0061);Loss of glycosylation at P542 (P = 0.0061);Loss of glycosylation at P542 (P = 0.0061);Loss of glycosylation at P542 (P = 0.0061);Loss of glycosylation at P542 (P = 0.0061);.;
MVP		0.81
ClinPred		0.84	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs764191178; hg19: chr16-2115545;