16-2065818-A-G

Variant names:

• chr16-2065818-A-G
• rs8063461
• NM_000548.5:c.1716+183A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000548.5(TSC2):​c.1716+183A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 152,016 control chromosomes in the GnomAD database, including 25,506 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.57 (25506 hom., cov: 31)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.448
• Publications: 13 publications found

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]

TSC2 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 16-2065818-A-G is Benign according to our data. Variant chr16-2065818-A-G is described in ClinVar as Benign. ClinVar VariationId is 677145.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.1716+183A>G		intron	N/A	NP_000539.2
	TSC2	NM_001406663.1		c.1716+183A>G		intron	N/A	NP_001393592.1
	TSC2	NM_001114382.3		c.1716+183A>G		intron	N/A	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.1716+183A>G		intron	N/A	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.1716+183A>G		intron	N/A	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.1716+183A>G		intron	N/A	ENSP00000384468.2

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86064 AN: 151898 Hom.: 25476 Cov.: 31

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.634

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.578

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.567 AC: 86119 AN: 152016 Hom.: 25506 Cov.: 31 AF XY: 0.571 AC XY: 42396 AN XY: 74308

African (AFR) AF: 0.383 AC: 15851 AN: 41426

American (AMR) AF: 0.684 AC: 10453 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 2108 AN: 3468

East Asian (EAS) AF: 0.842 AC: 4350 AN: 5164

South Asian (SAS) AF: 0.680 AC: 3278 AN: 4824

European-Finnish (FIN) AF: 0.586 AC: 6195 AN: 10574

Middle Eastern (MID) AF: 0.658 AC: 192 AN: 292

European-Non Finnish (NFE) AF: 0.616 AC: 41838 AN: 67964

Other (OTH) AF: 0.583 AC: 1227 AN: 2106

Alfa AF: 0.595 Hom.: 14788

Bravo AF: 0.564

Asia WGS AF: 0.763 AC: 2649 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.39
DANN	Benign	0.52
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8063461; hg19: chr16-2115819; COSMIC: COSV104375716;