rs7196184

Variant names:

• chr16-2072821-A-G
• rs7196184
• NM_000548.5:c.2221-28A>G

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.2221-28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,612,948 control chromosomes in the GnomAD database, including 4,960 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (2645 hom., cov: 33)
  • Exomes 𝑓: 0.011 (2315 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.136
• Publications: 3 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=-0.94).
• BP6: Variant 16-2072821-A-G is Benign according to our data. Variant chr16-2072821-A-G is described in ClinVar as Benign. ClinVar VariationId is 49604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.346 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.2221-28A>G		intron	N/A	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.2221-28A>G		intron	N/A	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.2221-28A>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.2221-28A>G		intron	N/A	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.2221-28A>G		intron	N/A	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.2221-28A>G		intron	N/A	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15380 AN: 151938 Hom.: 2619 Cov.: 33

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0408

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.0731

GnomAD2 exomes AF: 0.0266 AC: 6641 AN: 249626 AF XY: 0.0194

Gnomad AFR exome AF: 0.351

Gnomad AMR exome AF: 0.0193

Gnomad ASJ exome AF: 0.00529

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0107 AC: 15655 AN: 1460892 Hom.: 2315 Cov.: 31 AF XY: 0.00902 AC XY: 6558 AN XY: 726720

African (AFR) AF: 0.357 AC: 11963 AN: 33476

American (AMR) AF: 0.0218 AC: 976 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00685 AC: 179 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000812 AC: 70 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52568

Middle Eastern (MID) AF: 0.0163 AC: 93 AN: 5712

European-Non Finnish (NFE) AF: 0.000746 AC: 829 AN: 1111970

Other (OTH) AF: 0.0256 AC: 1543 AN: 60370

GnomAD4 genome AF: 0.102 AC: 15453 AN: 152056 Hom.: 2645 Cov.: 33 AF XY: 0.0994 AC XY: 7389 AN XY: 74340

African (AFR) AF: 0.351 AC: 14547 AN: 41468

American (AMR) AF: 0.0408 AC: 623 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 26 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 67968

Other (OTH) AF: 0.0723 AC: 152 AN: 2102

Alfa AF: 0.0839 Hom.: 986

Bravo AF: 0.115

Asia WGS AF: 0.0270 AC: 94 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.3
DANN	Benign	0.42
PhyloP100		-0.14
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7196184; hg19: chr16-2122822; COSMIC: COSV104375752;