16-2062543-A-G

Position:

• chr16-2062543-A-G

Variant summary

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

The NM_000548.5(TSC2):​c.1304A>G​(p.His435Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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. H435Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.95

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	UniProt
TSC2	NM_000548.5	c.1304A>G	p.His435Arg	missense_variant	13/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.1304A>G	p.His435Arg	missense_variant	13/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 17, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 1441967). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 435 of the TSC2 protein (p.His435Arg). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2024

The p.H435R variant (also known as c.1304A>G), located in coding exon 12 of the TSC2 gene, results from an A to G substitution at nucleotide position 1304. The histidine at codon 435 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	22
DANN	Benign	0.73
DEOGEN2	Uncertain	0.68	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;T;D;T;T;T;T;D;T;T;T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.8	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.62
Sift	Benign	0.49	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.43	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.55	P;.;.;.;B;P;.;.;B;B;.;.;.;.;.
Vest4		0.75
MutPred		0.41		Gain of MoRF binding (P = 0.0089);Gain of MoRF binding (P = 0.0089);Gain of MoRF binding (P = 0.0089);.;Gain of MoRF binding (P = 0.0089);Gain of MoRF binding (P = 0.0089);Gain of MoRF binding (P = 0.0089);Gain of MoRF binding (P = 0.0089);.;Gain of MoRF binding (P = 0.0089);Gain of MoRF binding (P = 0.0089);Gain of MoRF binding (P = 0.0089);Gain of MoRF binding (P = 0.0089);Gain of MoRF binding (P = 0.0089);.;
MVP		0.98
ClinPred		0.86	D
GERP RS		5.2
Varity_R		0.17
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr16-2112544;