16-2061778-T-C

Variant names:

• chr16-2061778-T-C
• rs17135764
• NM_000548.5:c.1120-93T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000548.5(TSC2):​c.1120-93T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 1,600,276 control chromosomes in the GnomAD database, including 288,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25175 hom., cov: 32)
  • Exomes 𝑓: 0.60 (263536 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -3.24
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-2061778-T-C is Benign according to our data. Variant chr16-2061778-T-C is described in ClinVar as Benign. ClinVar VariationId is 49143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.785 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.1120-93T>C		intron	N/A	NP_000539.2
	TSC2	NM_001406663.1		c.1120-93T>C		intron	N/A	NP_001393592.1
	TSC2	NM_001114382.3		c.1120-93T>C		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.1120-93T>C		intron	N/A	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.1120-93T>C		intron	N/A	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.1120-93T>C		intron	N/A	ENSP00000384468.2

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86516 AN: 151802 Hom.: 25141 Cov.: 32

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.698

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.662

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.578

GnomAD4 exome AF: 0.601 AC: 870903 AN: 1448356 Hom.: 263536 Cov.: 28 AF XY: 0.604 AC XY: 435283 AN XY: 720816

African (AFR) AF: 0.451 AC: 14999 AN: 33260

American (AMR) AF: 0.665 AC: 29407 AN: 44198

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 15842 AN: 26006

East Asian (EAS) AF: 0.780 AC: 30860 AN: 39554

South Asian (SAS) AF: 0.657 AC: 56158 AN: 85484

European-Finnish (FIN) AF: 0.581 AC: 29775 AN: 51204

Middle Eastern (MID) AF: 0.614 AC: 3422 AN: 5572

European-Non Finnish (NFE) AF: 0.593 AC: 654032 AN: 1103152

Other (OTH) AF: 0.608 AC: 36408 AN: 59926

GnomAD4 genome AF: 0.570 AC: 86589 AN: 151920 Hom.: 25175 Cov.: 32 AF XY: 0.572 AC XY: 42463 AN XY: 74274

African (AFR) AF: 0.452 AC: 18728 AN: 41406

American (AMR) AF: 0.607 AC: 9274 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2126 AN: 3468

East Asian (EAS) AF: 0.806 AC: 4142 AN: 5140

South Asian (SAS) AF: 0.663 AC: 3199 AN: 4824

European-Finnish (FIN) AF: 0.575 AC: 6086 AN: 10584

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.603 AC: 40981 AN: 67906

Other (OTH) AF: 0.583 AC: 1226 AN: 2104

Alfa AF: 0.591 Hom.: 90551

Bravo AF: 0.566

Asia WGS AF: 0.746 AC: 2588 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	not specified (1)
-	-	1	Tuberous sclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.050
DANN	Benign	0.34
PhyloP100		-3.2
Mutation Taster		=19/81	disease causing

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: rs17135764; hg19: chr16-2111779; COSMIC: COSV54772015;