rs769283410

Variant names:

• chr16-2081660-A-G
• rs769283410
• NM_000548.5:c.3676A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4 BP6 BS2

The NM_000548.5(TSC2):​c.3676A>G​(p.Met1226Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.88

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37168437).
• BP6: Variant 16-2081660-A-G is Benign according to our data. Variant chr16-2081660-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 405975.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.3676A>G	p.Met1226Val	missense_variant	Exon 31 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.3676A>G	p.Met1226Val	missense_variant	Exon 31 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250398 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460608 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726610

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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

Oct 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1226V variant (also known as c.3676A>G), located in coding exon 30 of the TSC2 gene, results from an A to G substitution at nucleotide position 3676. The methionine at codon 1226 is replaced by valine, 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. -

Tuberous sclerosis 2 Benign:1

Jun 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.3	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.025	D;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Uncertain	0.043	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.55	P;.;.;.;P;P;.;.;P;B;.;.;.;.;.
Vest4		0.69
MutPred		0.24		Loss of disorder (P = 0.0523);.;Loss of disorder (P = 0.0523);.;.;.;.;Loss of disorder (P = 0.0523);.;Loss of disorder (P = 0.0523);.;.;.;.;.;
MVP		0.92
ClinPred		0.59	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.72

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: rs769283410; hg19: chr16-2131661;