rs45517316

Variant names:

• chr16-2082512-C-G
• rs45517316
• NM_000548.5:c.3883+8C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-2082512-C-G
• chr16-2082512-C-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_000548.5(TSC2):​c.3883+8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,610,876 control chromosomes in the GnomAD database, including 68 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (32 hom., cov: 34)
  • Exomes 𝑓: 0.0012 (36 hom.)
• Consequence: TSC2 NM_000548.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001776
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 0.709
• 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=-0.79).
• BP6: Variant 16-2082512-C-G is Benign according to our data. Variant chr16-2082512-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 50027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0119 (1818/152348) while in subpopulation AFR AF = 0.0417 (1732/41580). AF 95% confidence interval is 0.04. There are 32 homozygotes in GnomAd4. There are 908 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1818 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.3883+8C>G		splice_region intron	N/A	NP_000539.2	P49815-1
	TSC2	NM_001406665.1		c.3759C>G	p.Ala1253Ala	synonymous	Exon 31 of 41	NP_001393594.1
	TSC2	NM_001406663.1		c.3880+8C>G		splice_region intron	N/A	NP_001393592.1	A0A2R8Y6C9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.3883+8C>G		splice_region intron	N/A	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.3814+714C>G		intron	N/A	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.3682+714C>G		intron	N/A	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1816 AN: 152230 Hom.: 32 Cov.: 34

Gnomad AFR AF: 0.0417

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.00299 AC: 744 AN: 248470 AF XY: 0.00224

Gnomad AFR exome AF: 0.0389

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00123 AC: 1795 AN: 1458528 Hom.: 36 Cov.: 31 AF XY: 0.00105 AC XY: 765 AN XY: 725664

African (AFR) AF: 0.0429 AC: 1435 AN: 33480

American (AMR) AF: 0.00295 AC: 132 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50238

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111902

Other (OTH) AF: 0.00293 AC: 177 AN: 60356

GnomAD4 genome AF: 0.0119 AC: 1818 AN: 152348 Hom.: 32 Cov.: 34 AF XY: 0.0122 AC XY: 908 AN XY: 74492

African (AFR) AF: 0.0417 AC: 1732 AN: 41580

American (AMR) AF: 0.00385 AC: 59 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68036

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.00503 Hom.: 4

Bravo AF: 0.0134

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	4	Tuberous sclerosis 2 (4)
-	-	2	Tuberous sclerosis syndrome (3)
-	-	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	-0.79
CADD	Benign	12
DANN	Benign	0.66
PhyloP100		0.71
PromoterAI		0.0010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.060		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: rs45517316; hg19: chr16-2132513; COSMIC: COSV105872708; COSMIC: COSV105872708;