16-2065505-C-T

Variant names:

• chr16-2065505-C-T
• rs45517185
• NM_000548.5:c.1600-14C>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.1600-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0621 in 1,610,218 control chromosomes in the GnomAD database, including 3,510 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (250 hom., cov: 32)
  • Exomes 𝑓: 0.063 (3260 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14 O:2
• Conservation: PhyloP100: -3.87
• Publications: 7 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=-0.86).
• BP6: Variant 16-2065505-C-T is Benign according to our data. Variant chr16-2065505-C-T is described in ClinVar as Benign. ClinVar VariationId is 50139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0619 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.1600-14C>T		intron	N/A	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.1600-14C>T		intron	N/A	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.1600-14C>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.1600-14C>T		intron	N/A	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.1600-14C>T		intron	N/A	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.1600-14C>T		intron	N/A	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.0483 AC: 7333 AN: 151808 Hom.: 249 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0473

Gnomad ASJ AF: 0.0933

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0663

Gnomad FIN AF: 0.0925

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0635

Gnomad OTH AF: 0.0503

GnomAD2 exomes AF: 0.0565 AC: 14111 AN: 249674 AF XY: 0.0589

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.0328

Gnomad ASJ exome AF: 0.0990

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.0864

Gnomad NFE exome AF: 0.0664

Gnomad OTH exome AF: 0.0641

GnomAD4 exome AF: 0.0635 AC: 92601 AN: 1458296 Hom.: 3260 Cov.: 32 AF XY: 0.0636 AC XY: 46162 AN XY: 725560

African (AFR) AF: 0.0106 AC: 355 AN: 33426

American (AMR) AF: 0.0334 AC: 1492 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 2611 AN: 26104

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39654

South Asian (SAS) AF: 0.0682 AC: 5877 AN: 86202

European-Finnish (FIN) AF: 0.0835 AC: 4415 AN: 52904

Middle Eastern (MID) AF: 0.102 AC: 589 AN: 5762

European-Non Finnish (NFE) AF: 0.0664 AC: 73643 AN: 1109316

Other (OTH) AF: 0.0599 AC: 3608 AN: 60242

GnomAD4 genome AF: 0.0483 AC: 7333 AN: 151922 Hom.: 250 Cov.: 32 AF XY: 0.0496 AC XY: 3680 AN XY: 74222

African (AFR) AF: 0.0130 AC: 538 AN: 41440

American (AMR) AF: 0.0473 AC: 721 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0933 AC: 323 AN: 3462

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.0666 AC: 321 AN: 4818

European-Finnish (FIN) AF: 0.0925 AC: 972 AN: 10504

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0635 AC: 4313 AN: 67942

Other (OTH) AF: 0.0498 AC: 105 AN: 2108

Alfa AF: 0.0393 Hom.: 42

Bravo AF: 0.0432

Asia WGS AF: 0.0370 AC: 127 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Tuberous sclerosis 2 (4)
-	-	2	not provided (2)
-	-	2	Tuberous sclerosis syndrome (3)
-	-	-	Tuberous sclerosis syndrome;C0751674:Lymphangiomyomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.010
DANN	Benign	0.31
PhyloP100		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=99/1	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: rs45517185; hg19: chr16-2115506; COSMIC: COSV54756558;