rs397515119

Variant names:

• chr16-2080418-T-TC
• rs397515119
• NM_000548.5:c.3610+42dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000548.5(TSC2):​c.3610+42dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00705 in 1,604,800 control chromosomes in the GnomAD database, including 730 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (362 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (368 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -2.11
• Publications: 0 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 -16 ACMG points.

• BP6: Variant 16-2080418-T-TC is Benign according to our data. Variant chr16-2080418-T-TC is described in ClinVar as Benign. ClinVar VariationId is 65163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 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.3610+42dupC		intron	N/A	NP_000539.2
	TSC2	NM_001406663.1		c.3607+42dupC		intron	N/A	NP_001393592.1
	TSC2	NM_001114382.3		c.3610+42dupC		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.3610+42dupC		intron	N/A	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.3610+42dupC		intron	N/A	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.3478+42dupC		intron	N/A	ENSP00000384468.2

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5642 AN: 152026 Hom.: 360 Cov.: 33

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0274

GnomAD2 exomes AF: 0.00977 AC: 2346 AN: 240186 AF XY: 0.00739

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.00702

Gnomad ASJ exome AF: 0.000918

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000488

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00390 AC: 5659 AN: 1452684 Hom.: 368 Cov.: 31 AF XY: 0.00340 AC XY: 2453 AN XY: 722038

African (AFR) AF: 0.136 AC: 4524 AN: 33282

American (AMR) AF: 0.00791 AC: 353 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.000882 AC: 23 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.000221 AC: 19 AN: 86052

European-Finnish (FIN) AF: 0.0000197 AC: 1 AN: 50744

Middle Eastern (MID) AF: 0.00755 AC: 32 AN: 4238

European-Non Finnish (NFE) AF: 0.000193 AC: 214 AN: 1108100

Other (OTH) AF: 0.00821 AC: 493 AN: 60016

GnomAD4 genome AF: 0.0372 AC: 5660 AN: 152116 Hom.: 362 Cov.: 33 AF XY: 0.0351 AC XY: 2608 AN XY: 74364

African (AFR) AF: 0.128 AC: 5318 AN: 41460

American (AMR) AF: 0.0160 AC: 245 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 68006

Other (OTH) AF: 0.0271 AC: 57 AN: 2104

Alfa AF: 0.0168 Hom.: 32

Bravo AF: 0.0438

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.1
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: rs397515119; hg19: chr16-2130419; COSMIC: COSV104375823; COSMIC: COSV104375823;