16-2075787-C-T

Variant names:

• chr16-2075787-C-T
• rs13331451
• NM_000548.5:c.2546-12C>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.2546-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0917 in 1,611,716 control chromosomes in the GnomAD database, including 15,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (6593 hom., cov: 32)
  • Exomes 𝑓: 0.080 (9103 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Scores: Splicing: ADA: 0.00001352
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: -0.551
• Publications: 14 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=-0.9).
• BP6: Variant 16-2075787-C-T is Benign according to our data. Variant chr16-2075787-C-T is described in ClinVar as Benign. ClinVar VariationId is 49214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.537 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.2546-12C>T		intron	N/A	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.2546-12C>T		intron	N/A	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.2546-12C>T		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.2546-12C>T		intron	N/A	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.2546-12C>T		intron	N/A	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.2546-12C>T		intron	N/A	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30916 AN: 152016 Hom.: 6566 Cov.: 32

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.0712

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.0487

Gnomad FIN AF: 0.0993

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0685

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.0953 AC: 23714 AN: 248848 AF XY: 0.0863

Gnomad AFR exome AF: 0.549

Gnomad AMR exome AF: 0.0637

Gnomad ASJ exome AF: 0.0734

Gnomad EAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0974

Gnomad NFE exome AF: 0.0712

Gnomad OTH exome AF: 0.0792

GnomAD4 exome AF: 0.0801 AC: 116840 AN: 1459582 Hom.: 9103 Cov.: 33 AF XY: 0.0774 AC XY: 56226 AN XY: 726164

African (AFR) AF: 0.560 AC: 18753 AN: 33468

American (AMR) AF: 0.0692 AC: 3095 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0754 AC: 1969 AN: 26126

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39694

South Asian (SAS) AF: 0.0483 AC: 4164 AN: 86256

European-Finnish (FIN) AF: 0.0979 AC: 5030 AN: 51392

Middle Eastern (MID) AF: 0.102 AC: 587 AN: 5766

European-Non Finnish (NFE) AF: 0.0696 AC: 77332 AN: 1111822

Other (OTH) AF: 0.0978 AC: 5902 AN: 60348

GnomAD4 genome AF: 0.204 AC: 30995 AN: 152134 Hom.: 6593 Cov.: 32 AF XY: 0.201 AC XY: 14967 AN XY: 74376

African (AFR) AF: 0.542 AC: 22511 AN: 41498

American (AMR) AF: 0.122 AC: 1862 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0712 AC: 247 AN: 3470

East Asian (EAS) AF: 0.000775 AC: 4 AN: 5164

South Asian (SAS) AF: 0.0484 AC: 233 AN: 4818

European-Finnish (FIN) AF: 0.0993 AC: 1054 AN: 10614

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0685 AC: 4656 AN: 67964

Other (OTH) AF: 0.169 AC: 356 AN: 2106

Alfa AF: 0.118 Hom.: 3964

Bravo AF: 0.218

Asia WGS AF: 0.0680 AC: 237 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Tuberous sclerosis 2 (4)
-	-	3	not provided (3)
-	-	3	Tuberous sclerosis syndrome (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.32
DANN	Benign	0.47
PhyloP100		-0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0020
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: rs13331451; hg19: chr16-2125788; COSMIC: COSV54756570;