rs752693719

Positions:

• chr16-2084652-G-A
• chr16-2084652-G-C
• chr16-2084652-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000548.5(TSC2):​c.4430G>A​(p.Arg1477Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,447,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1477S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.96

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1468007).
• BP6: Variant 16-2084652-G-A is Benign according to our data. Variant chr16-2084652-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 578769.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.4430G>A	p.Arg1477Lys	missense_variant	34/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.4430G>A	p.Arg1477Lys	missense_variant	34/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000841 AC: 2 AN: 237826 Hom.: 0 AF XY: 0.00000768 AC XY: 1 AN XY: 130254

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447044 Hom.: 0 Cov.: 33 AF XY: 0.00000278 AC XY: 2 AN XY: 720350

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 03, 2022

The p.R1477K variant (also known as c.4430G>A), located in coding exon 33 of the TSC2 gene, results from a G to A substitution at nucleotide position 4430. The arginine at codon 1477 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is conserved. 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. -

Tuberous sclerosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	17
DANN	Benign	0.76
DEOGEN2	Uncertain	0.46	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.75	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.5	L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.89	D;D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.56
Sift	Benign	0.61	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.77	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.99	D;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.26
MutPred		0.34		Gain of ubiquitination at R1477 (P = 0.0289);.;.;.;.;.;.;Gain of ubiquitination at R1477 (P = 0.0289);.;.;.;.;.;.;.;
MVP		0.94
ClinPred		0.034	T
GERP RS		3.9
Varity_R		0.076
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs752693719; hg19: chr16-2134653;