rs7196184

chr16-2072821-A-G

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.2221-28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,612,948 control chromosomes in the GnomAD database, including 4,960 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (2645 hom., cov: 33)
  • Exomes 𝑓: 0.011 (2315 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.136

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=-0.94).
• BP6: Variant 16-2072821-A-G is Benign according to our data. Variant chr16-2072821-A-G is described in ClinVar as [Benign]. Clinvar id is 49604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2072821-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.2221-28A>G		intron_variant		ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.2221-28A>G		intron_variant		5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15380 AN: 151938 Hom.: 2619 Cov.: 33

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0408

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.0731

GnomAD3 exomes AF: 0.0266 AC: 6641 AN: 249626 Hom.: 1005 AF XY: 0.0194 AC XY: 2624 AN XY: 135336

Gnomad AFR exome AF: 0.351

Gnomad AMR exome AF: 0.0193

Gnomad ASJ exome AF: 0.00529

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0107 AC: 15655 AN: 1460892 Hom.: 2315 Cov.: 31 AF XY: 0.00902 AC XY: 6558 AN XY: 726720

Gnomad4 AFR exome AF: 0.357

Gnomad4 AMR exome AF: 0.0218

Gnomad4 ASJ exome AF: 0.00685

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000746

Gnomad4 OTH exome AF: 0.0256

GnomAD4 genome AF: 0.102 AC: 15453 AN: 152056 Hom.: 2645 Cov.: 33 AF XY: 0.0994 AC XY: 7389 AN XY: 74340

Gnomad4 AFR AF: 0.351

Gnomad4 AMR AF: 0.0408

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.0723

Alfa AF: 0.0761 Hom.: 425

Bravo AF: 0.115

Asia WGS AF: 0.0270 AC: 94 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 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. -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	1.3
Dann	Benign	0.42

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: rs7196184; hg19: chr16-2122822; COSMIC: COSV104375752; COSMIC: COSV104375752;