chr16-2086801-A-G

Position:

• chr16-2086801-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000548.5(TSC2):​c.4919A>G​(p.His1640Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1640P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.24

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a domain Rap-GAP (size 227) in uniprot entity TSC2_HUMAN there are 284 pathogenic changes around while only 47 benign (86%) in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2086801-A-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 16-2086801-A-G is Pathogenic according to our data. Variant chr16-2086801-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 547828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2086801-A-G is described in Lovd as [Pathogenic]. Variant chr16-2086801-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4919A>G	p.His1640Arg	missense_variant	38/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4919A>G	p.His1640Arg	missense_variant	38/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2017

The p.H1640R variant (also known as c.4919A>G), located in coding exon 37 of the TSC2 gene, results from an A to G substitution at nucleotide position 4919. The histidine at codon 1640 is replaced by arginine, an amino acid with highly similar properties. This alteration was identified in at least one individual meeting diagnostic criteria for tuberous sclerosis (Ambry internal data). Internal structural analysis indicates that this variant disrupts a known functional residue in a related paralog (Ambry internal data; Daumke O et al. Nature, 2004 May;429:197-201). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.9	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.99	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.96
MutPred		0.90		Gain of MoRF binding (P = 0.0273);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.99
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.93

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

LitVar

Other links and lift over

dbSNP: rs794727602; hg19: chr16-2136802;