rs1800724

Variant names:

• chr16-2083639-C-G
• rs1800724
• NM_000548.5:c.3884-56C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-2083639-C-G
• chr16-2083639-C-A
• chr16-2083639-C-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.3884-56C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0654 in 1,552,426 control chromosomes in the GnomAD database, including 3,724 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (271 hom., cov: 34)
  • Exomes 𝑓: 0.067 (3453 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.36
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-2083639-C-G is Benign according to our data. Variant chr16-2083639-C-G is described in ClinVar as Benign. ClinVar VariationId is 49900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0671 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.3884-56C>G		intron	N/A	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.3881-56C>G		intron	N/A	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.3815-56C>G		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.3884-56C>G		intron	N/A	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.3815-56C>G		intron	N/A	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.3683-56C>G		intron	N/A	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.0508 AC: 7730 AN: 152150 Hom.: 271 Cov.: 34

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0437

Gnomad ASJ AF: 0.0864

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0654

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0687

Gnomad OTH AF: 0.0454

GnomAD2 exomes AF: 0.0586 AC: 9275 AN: 158208 AF XY: 0.0610

Gnomad AFR exome AF: 0.00941

Gnomad AMR exome AF: 0.0296

Gnomad ASJ exome AF: 0.0917

Gnomad EAS exome AF: 0.000251

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.0701

Gnomad OTH exome AF: 0.0580

GnomAD4 exome AF: 0.0670 AC: 93838 AN: 1400158 Hom.: 3453 Cov.: 32 AF XY: 0.0672 AC XY: 46458 AN XY: 690864

African (AFR) AF: 0.00952 AC: 304 AN: 31934

American (AMR) AF: 0.0301 AC: 1083 AN: 35966

Ashkenazi Jewish (ASJ) AF: 0.0932 AC: 2345 AN: 25152

East Asian (EAS) AF: 0.000193 AC: 7 AN: 36304

South Asian (SAS) AF: 0.0672 AC: 5340 AN: 79458

European-Finnish (FIN) AF: 0.108 AC: 5038 AN: 46818

Middle Eastern (MID) AF: 0.0605 AC: 343 AN: 5672

European-Non Finnish (NFE) AF: 0.0702 AC: 75848 AN: 1080720

Other (OTH) AF: 0.0607 AC: 3530 AN: 58134

GnomAD4 genome AF: 0.0507 AC: 7727 AN: 152268 Hom.: 271 Cov.: 34 AF XY: 0.0525 AC XY: 3910 AN XY: 74444

African (AFR) AF: 0.0126 AC: 522 AN: 41570

American (AMR) AF: 0.0437 AC: 669 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0864 AC: 300 AN: 3472

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5170

South Asian (SAS) AF: 0.0655 AC: 316 AN: 4828

European-Finnish (FIN) AF: 0.106 AC: 1126 AN: 10614

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0687 AC: 4671 AN: 67990

Other (OTH) AF: 0.0449 AC: 95 AN: 2114

Alfa AF: 0.0599 Hom.: 61

Bravo AF: 0.0425

Asia WGS AF: 0.0330 AC: 113 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.9
DANN	Benign	0.64
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1800724; hg19: chr16-2133640; COSMIC: COSV54756610; COSMIC: COSV54756610;