rs1800720

Variant names:

• chr16-2055399-C-T
• rs1800720
• NM_000548.5:c.482-3C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2055399-C-T
• chr16-2055399-C-A

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.482-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0951 in 1,613,492 control chromosomes in the GnomAD database, including 8,382 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1381 hom., cov: 32)
  • Exomes 𝑓: 0.092 (7001 hom.)
• Consequence: TSC2 NM_000548.5 splice_region, intron
• Scores: Splicing: ADA: 0.0006049
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:3
• Conservation: PhyloP100: 0.111
• Publications: 25 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• 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=-0.81).
• BP6: Variant 16-2055399-C-T is Benign according to our data. Variant chr16-2055399-C-T is described in ClinVar as Benign. ClinVar VariationId is 49957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 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.482-3C>T		splice_region intron	N/A	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.482-3C>T		splice_region intron	N/A	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.482-3C>T		splice_region 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.482-3C>T		splice_region intron	N/A	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.482-3C>T		splice_region intron	N/A	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.482-3C>T		splice_region intron	N/A	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18710 AN: 152068 Hom.: 1375 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0949

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0280

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0974

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.0868 AC: 21836 AN: 251444 AF XY: 0.0840

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0571

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.0966

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.0922 AC: 134667 AN: 1461306 Hom.: 7001 Cov.: 31 AF XY: 0.0898 AC XY: 65260 AN XY: 727010

African (AFR) AF: 0.203 AC: 6809 AN: 33466

American (AMR) AF: 0.0622 AC: 2781 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3665 AN: 26124

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.0291 AC: 2511 AN: 86242

European-Finnish (FIN) AF: 0.126 AC: 6712 AN: 53392

Middle Eastern (MID) AF: 0.133 AC: 763 AN: 5738

European-Non Finnish (NFE) AF: 0.0950 AC: 105611 AN: 1111544

Other (OTH) AF: 0.0962 AC: 5811 AN: 60378

GnomAD4 genome AF: 0.123 AC: 18740 AN: 152186 Hom.: 1381 Cov.: 32 AF XY: 0.122 AC XY: 9081 AN XY: 74388

African (AFR) AF: 0.198 AC: 8200 AN: 41500

American (AMR) AF: 0.0947 AC: 1449 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 508 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.0278 AC: 134 AN: 4824

European-Finnish (FIN) AF: 0.135 AC: 1435 AN: 10592

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0974 AC: 6624 AN: 68000

Other (OTH) AF: 0.125 AC: 265 AN: 2114

Alfa AF: 0.118 Hom.: 2293

Bravo AF: 0.125

Asia WGS AF: 0.0250 AC: 88 AN: 3478

EpiCase AF: 0.106

EpiControl AF: 0.107

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	Tuberous sclerosis 2 (5)
-	-	4	not provided (4)
-	-	2	Tuberous sclerosis syndrome (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	-	Neoplasm of brain (1)
-	-	-	Tuberous sclerosis syndrome;C0751674:Lymphangiomyomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.6
DANN	Benign	0.32
PhyloP100		0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00060
dbscSNV1_RF	Benign	0.074
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1800720;

hg19: chr16-2105400;

COSMIC: COSV54755039;