rs45475501

Variant names:

• chr16-2087901-G-A
• rs45475501
• NM_000548.5:c.5028G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000548.5(TSC2):​c.5028G>A​(p.Leu1676Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.000397 in 1,611,748 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1676L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (2 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:17 O:1
• Conservation: PhyloP100: 3.83
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 16-2087901-G-A is Benign according to our data. Variant chr16-2087901-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 50004.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000296 (45/151850) while in subpopulation EAS AF = 0.00214 (11/5130). AF 95% confidence interval is 0.0012. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 45 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.5028G>A	p.Leu1676Leu	synonymous	Exon 39 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.5025G>A	p.Leu1675Leu	synonymous	Exon 39 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.4959G>A	p.Leu1653Leu	synonymous	Exon 38 of 41	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.5028G>A	p.Leu1676Leu	synonymous	Exon 39 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.4959G>A	p.Leu1653Leu	synonymous	Exon 38 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.4827G>A	p.Leu1609Leu	synonymous	Exon 37 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 151736 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000729

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00233

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000417 AC: 104 AN: 249670 AF XY: 0.000457

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00208

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000391

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000408 AC: 595 AN: 1459898 Hom.: 2 Cov.: 32 AF XY: 0.000441 AC XY: 320 AN XY: 726226

African (AFR) AF: 0.000180 AC: 6 AN: 33376

American (AMR) AF: 0.000157 AC: 7 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00332 AC: 131 AN: 39448

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86202

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52096

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.000339 AC: 377 AN: 1111822

Other (OTH) AF: 0.000447 AC: 27 AN: 60348

GnomAD4 genome AF: 0.000296 AC: 45 AN: 151850 Hom.: 0 Cov.: 33 AF XY: 0.000256 AC XY: 19 AN XY: 74236

African (AFR) AF: 0.0000727 AC: 3 AN: 41244

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00214 AC: 11 AN: 5130

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000383 AC: 26 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000373 Hom.: 0

Bravo AF: 0.000359

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	Tuberous sclerosis 2 (6)
-	-	5	not specified (5)
-	-	3	Tuberous sclerosis syndrome (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	not provided (1)
-	-	1	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.82
PhyloP100		3.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs45475501; hg19: chr16-2137902;