rs876659087

chr16-2083792-C-Gchr16-2083792-C-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.3981C>G(p.Asp1327Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. D1327G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.592

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=0.1564104).
• BP6: Variant 16-2083792-C-G is Benign according to our data. Variant chr16-2083792-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 231318.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}. Variant chr16-2083792-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.3981C>G	p.Asp1327Glu	missense_variant	33/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.3981C>G	p.Asp1327Glu	missense_variant	33/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459212 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 725744

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2019

The p.D1327E variant (also known as c.3981C>G), located in coding exon 32 of the TSC2 gene, results from a C to G substitution at nucleotide position 3981. The aspartic acid at codon 1327 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in limited sequence alignment. 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	0.099
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	0.86
Dann	Benign	0.74
DEOGEN2	Benign	0.37	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.73	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.26	N;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.57
Sift	Benign	0.25	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.79	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.0010	B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.14
MutPred		0.14		Loss of loop (P = 0.0128);.;.;.;.;.;.;Loss of loop (P = 0.0128);.;.;.;.;.;.;.;
MVP		0.96
ClinPred		0.035	T
GERP RS		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.095
gMVP		0.19

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: rs876659087; hg19: chr16-2133793;