rs2074968

chr16-2060570-C-Gchr16-2060570-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000548.5(TSC2):c.976-100C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,595,738 control chromosomes in the GnomAD database, including 257,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22385 hom., cov: 31)
  • Exomes 𝑓: 0.57 (234848 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.93

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-2060570-C-G is Benign according to our data. Variant chr16-2060570-C-G is described in ClinVar as [Benign]. Clinvar id is 675047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2060570-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.976-100C>G		intron_variant		ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.976-100C>G		intron_variant		5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.538 AC: 81643 AN: 151816 Hom.: 22360 Cov.: 31

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.648

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.713

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.548

GnomAD4 exome AF: 0.568 AC: 820770 AN: 1443804 Hom.: 234848 AF XY: 0.572 AC XY: 411257 AN XY: 718734

Gnomad4 AFR exome AF: 0.441

Gnomad4 AMR exome AF: 0.468

Gnomad4 ASJ exome AF: 0.600

Gnomad4 EAS exome AF: 0.683

Gnomad4 SAS exome AF: 0.649

Gnomad4 FIN exome AF: 0.553

Gnomad4 NFE exome AF: 0.565

Gnomad4 OTH exome AF: 0.575

GnomAD4 genome AF: 0.538 AC: 81701 AN: 151934 Hom.: 22385 Cov.: 31 AF XY: 0.539 AC XY: 39990 AN XY: 74224

Gnomad4 AFR AF: 0.442

Gnomad4 AMR AF: 0.502

Gnomad4 ASJ AF: 0.601

Gnomad4 EAS AF: 0.713

Gnomad4 SAS AF: 0.651

Gnomad4 FIN AF: 0.542

Gnomad4 NFE AF: 0.577

Gnomad4 OTH AF: 0.553

Alfa AF: 0.444 Hom.: 1312

Bravo AF: 0.526

Asia WGS AF: 0.699 AC: 2429 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.15
Dann	Benign	0.45

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: rs2074968; hg19: chr16-2110571; COSMIC: COSV54765122; COSMIC: COSV54765122;