rs186681035

chr16-2071977-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000548.5(TSC2):c.2097+43A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,537,292 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (8 hom., cov: 33)
  • Exomes 𝑓: 0.011 (104 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.285

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=-0.9).
• BP6: Variant 16-2071977-A-G is Benign according to our data. Variant chr16-2071977-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 64899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071977-A-G is described in Lovd as [Likely_benign]. Variant chr16-2071977-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00886 (1350/152340) while in subpopulation NFE AF= 0.013 (884/68024). AF 95% confidence interval is 0.0123. There are 8 homozygotes in gnomad4. There are 658 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1349 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.2097+43A>G		intron_variant		ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.2097+43A>G		intron_variant		5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.00886 AC: 1349 AN: 152222 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00915 AC: 1347 AN: 147266 Hom.: 11 AF XY: 0.00916 AC XY: 731 AN XY: 79764

Gnomad AFR exome AF: 0.00242

Gnomad AMR exome AF: 0.00285

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00475

Gnomad FIN exome AF: 0.0261

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.00768

GnomAD4 exome AF: 0.0112 AC: 15526 AN: 1384952 Hom.: 104 Cov.: 33 AF XY: 0.0109 AC XY: 7459 AN XY: 681390

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00341

Gnomad4 ASJ exome AF: 0.0104

Gnomad4 EAS exome AF: 0.0000276

Gnomad4 SAS exome AF: 0.00492

Gnomad4 FIN exome AF: 0.0229

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.00956

GnomAD4 genome AF: 0.00886 AC: 1350 AN: 152340 Hom.: 8 Cov.: 33 AF XY: 0.00883 AC XY: 658 AN XY: 74486

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00627

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0205

Gnomad4 NFE AF: 0.0130

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.0102 Hom.: 1

Bravo AF: 0.00743

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely 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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 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	-0.90
Cadd	Benign	0.52
Dann	Benign	0.41

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: rs186681035; hg19: chr16-2121978; COSMIC: COSV104375820; COSMIC: COSV104375820;