chr16-2065480-C-T

Variant names:

• chr16-2065480-C-T
• rs45477195
• NM_000548.5:c.1600-39C>T

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.1600-39C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.087 in 1,502,856 control chromosomes in the GnomAD database, including 6,350 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (507 hom., cov: 31)
  • Exomes 𝑓: 0.089 (5843 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.549
• Publications: 12 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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=-0.82).
• BP6: Variant 16-2065480-C-T is Benign according to our data. Variant chr16-2065480-C-T is described in ClinVar as Benign. ClinVar VariationId is 49695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0953 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.1600-39C>T		intron	N/A	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.1600-39C>T		intron	N/A	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.1600-39C>T		intron	N/A	NP_001107854.1	P49815-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.1600-39C>T		intron	N/A	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.1600-39C>T		intron	N/A	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.1600-39C>T		intron	N/A	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.0732 AC: 11031 AN: 150744 Hom.: 506 Cov.: 31

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.0828

Gnomad AMR AF: 0.0733

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.000775

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0972

Gnomad OTH AF: 0.0881

GnomAD2 exomes AF: 0.0737 AC: 18357 AN: 248940 AF XY: 0.0746

Gnomad AFR exome AF: 0.0248

Gnomad AMR exome AF: 0.0483

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.0967

Gnomad OTH exome AF: 0.0983

GnomAD4 exome AF: 0.0886 AC: 119737 AN: 1352024 Hom.: 5843 Cov.: 24 AF XY: 0.0872 AC XY: 59042 AN XY: 677172

African (AFR) AF: 0.0249 AC: 784 AN: 31424

American (AMR) AF: 0.0522 AC: 2317 AN: 44366

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3587 AN: 25304

East Asian (EAS) AF: 0.0000520 AC: 2 AN: 38466

South Asian (SAS) AF: 0.0289 AC: 2433 AN: 84048

European-Finnish (FIN) AF: 0.125 AC: 6485 AN: 51800

Middle Eastern (MID) AF: 0.123 AC: 681 AN: 5556

European-Non Finnish (NFE) AF: 0.0972 AC: 98570 AN: 1014478

Other (OTH) AF: 0.0862 AC: 4878 AN: 56582

GnomAD4 genome AF: 0.0732 AC: 11040 AN: 150832 Hom.: 507 Cov.: 31 AF XY: 0.0730 AC XY: 5371 AN XY: 73558

African (AFR) AF: 0.0263 AC: 1079 AN: 41034

American (AMR) AF: 0.0732 AC: 1108 AN: 15134

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 511 AN: 3460

East Asian (EAS) AF: 0.000776 AC: 4 AN: 5152

South Asian (SAS) AF: 0.0274 AC: 131 AN: 4782

European-Finnish (FIN) AF: 0.129 AC: 1311 AN: 10156

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0973 AC: 6599 AN: 67828

Other (OTH) AF: 0.0872 AC: 182 AN: 2086

Alfa AF: 0.0719 Hom.: 242

Bravo AF: 0.0681

Asia WGS AF: 0.0140 AC: 50 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.3
DANN	Benign	0.39
PhyloP100		0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs45477195; hg19: chr16-2115481; COSMIC: COSV54755055;