rs45517097

Variant names:

• chr16-2053344-C-T
• rs45517097
• NM_000548.5:c.228C>T

Variant summary

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

The NM_001406680.1(TSC2):​c.-589C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,580,544 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (9 hom.)
• Consequence: TSC2 NM_001406680.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20 O:1
• Conservation: PhyloP100: -0.100
• Publications: 10 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=-0.58).
• BP6: Variant 16-2053344-C-T is Benign according to our data. Variant chr16-2053344-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49202.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 = 0.0028 (426/152344) while in subpopulation NFE AF = 0.00153 (104/68034). AF 95% confidence interval is 0.00129. There are 6 homozygotes in GnomAd4. There are 297 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 426 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406680.1. 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.228C>T	p.His76His	splice_region synonymous	Exon 4 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406680.1		c.-589C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 42	NP_001393609.1
	TSC2	NM_001406681.1		c.-218C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 40	NP_001393610.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.228C>T	p.His76His	splice_region synonymous	Exon 4 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.228C>T	p.His76His	splice_region synonymous	Exon 4 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.228C>T	p.His76His	splice_region synonymous	Exon 4 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 152226 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0288

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00332 AC: 657 AN: 198132 AF XY: 0.00310

Gnomad AFR exome AF: 0.000253

Gnomad AMR exome AF: 0.000206

Gnomad ASJ exome AF: 0.000222

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0232

Gnomad NFE exome AF: 0.00272

Gnomad OTH exome AF: 0.00273

GnomAD4 exome AF: 0.00195 AC: 2778 AN: 1428200 Hom.: 9 Cov.: 31 AF XY: 0.00182 AC XY: 1287 AN XY: 707354

African (AFR) AF: 0.0000609 AC: 2 AN: 32822

American (AMR) AF: 0.000226 AC: 9 AN: 39866

Ashkenazi Jewish (ASJ) AF: 0.000118 AC: 3 AN: 25502

East Asian (EAS) AF: 0.00 AC: 0 AN: 38046

South Asian (SAS) AF: 0.0000615 AC: 5 AN: 81270

European-Finnish (FIN) AF: 0.0208 AC: 1049 AN: 50478

Middle Eastern (MID) AF: 0.000206 AC: 1 AN: 4854

European-Non Finnish (NFE) AF: 0.00147 AC: 1615 AN: 1096308

Other (OTH) AF: 0.00159 AC: 94 AN: 59054

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152344 Hom.: 6 Cov.: 33 AF XY: 0.00399 AC XY: 297 AN XY: 74502

African (AFR) AF: 0.000241 AC: 10 AN: 41578

American (AMR) AF: 0.000196 AC: 3 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.0288 AC: 306 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00153 AC: 104 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.000801

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	not provided (5)
-	-	4	Tuberous sclerosis 2 (4)
-	-	2	Tuberous sclerosis syndrome (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	6.3
DANN	Benign	0.69
PhyloP100		-0.10
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs45517097; hg19: chr16-2103345; COSMIC: COSV54776279;