rs45482793

Variant names:

• chr16-2085072-C-T
• rs45482793
• NM_000548.5:c.4569+46C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2085072-C-T
• chr16-2085072-C-A
• chr16-2085072-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000548.5(TSC2):​c.4569+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,610,540 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 34)
  • Exomes 𝑓: 0.014 (169 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.450
• Publications: 4 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=-0.88).
• BP6: Variant 16-2085072-C-T is Benign according to our data. Variant chr16-2085072-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0105 (1595/152328) while in subpopulation NFE AF = 0.0187 (1270/68024). AF 95% confidence interval is 0.0178. There are 14 homozygotes in GnomAd4. There are 726 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1595 AD gene.

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.4569+46C>T		intron	N/A	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.4566+46C>T		intron	N/A	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.4500+46C>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.4569+46C>T		intron	N/A	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.4500+46C>T		intron	N/A	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.4368+46C>T		intron	N/A	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1595 AN: 152210 Hom.: 14 Cov.: 34

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0187

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0103 AC: 2564 AN: 249256 AF XY: 0.0102

Gnomad AFR exome AF: 0.00255

Gnomad AMR exome AF: 0.00501

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00714

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0120

GnomAD4 exome AF: 0.0139 AC: 20268 AN: 1458212 Hom.: 169 Cov.: 32 AF XY: 0.0137 AC XY: 9910 AN XY: 725618

African (AFR) AF: 0.00260 AC: 87 AN: 33404

American (AMR) AF: 0.00503 AC: 225 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 284 AN: 26122

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39680

South Asian (SAS) AF: 0.00355 AC: 306 AN: 86172

European-Finnish (FIN) AF: 0.00760 AC: 397 AN: 52226

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5762

European-Non Finnish (NFE) AF: 0.0164 AC: 18213 AN: 1109872

Other (OTH) AF: 0.0120 AC: 726 AN: 60278

GnomAD4 genome AF: 0.0105 AC: 1595 AN: 152328 Hom.: 14 Cov.: 34 AF XY: 0.00975 AC XY: 726 AN XY: 74484

African (AFR) AF: 0.00233 AC: 97 AN: 41570

American (AMR) AF: 0.00601 AC: 92 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.00527 AC: 56 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0187 AC: 1270 AN: 68024

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.0151 Hom.: 43

Bravo AF: 0.00958

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.76
DANN	Benign	0.36
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism

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: rs45482793; hg19: chr16-2135073; COSMIC: COSV51923988; COSMIC: COSV51923988;