16-2075768-G-A

Variant names:

• chr16-2075768-G-A
• rs145738496
• NM_000548.5:c.2546-31G>A

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.2546-31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,609,360 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (9 hom., cov: 32)
  • Exomes 𝑓: 0.012 (131 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.104
• 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: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, 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=-0.8).
• BP6: Variant 16-2075768-G-A is Benign according to our data. Variant chr16-2075768-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 65156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00978 (1488/152224) while in subpopulation NFE AF = 0.0141 (959/68004). AF 95% confidence interval is 0.0134. There are 9 homozygotes in GnomAd4. There are 707 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1488 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.2546-31G>A		intron	N/A	NP_000539.2
	TSC2	NM_001406663.1		c.2546-31G>A		intron	N/A	NP_001393592.1
	TSC2	NM_001114382.3		c.2546-31G>A		intron	N/A	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.2546-31G>A		intron	N/A	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.2546-31G>A		intron	N/A	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.2546-31G>A		intron	N/A	ENSP00000384468.2

Frequencies

GnomAD3 genomes AF: 0.00979 AC: 1489 AN: 152106 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.00863

GnomAD2 exomes AF: 0.0105 AC: 2594 AN: 246860 AF XY: 0.0103

Gnomad AFR exome AF: 0.00245

Gnomad AMR exome AF: 0.00388

Gnomad ASJ exome AF: 0.0158

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0227

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.0115 AC: 16767 AN: 1457136 Hom.: 131 Cov.: 31 AF XY: 0.0113 AC XY: 8203 AN XY: 725124

African (AFR) AF: 0.00164 AC: 55 AN: 33448

American (AMR) AF: 0.00445 AC: 199 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 400 AN: 26106

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39682

South Asian (SAS) AF: 0.00226 AC: 195 AN: 86232

European-Finnish (FIN) AF: 0.0229 AC: 1144 AN: 49952

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5764

European-Non Finnish (NFE) AF: 0.0128 AC: 14176 AN: 1110966

Other (OTH) AF: 0.00959 AC: 578 AN: 60284

GnomAD4 genome AF: 0.00978 AC: 1488 AN: 152224 Hom.: 9 Cov.: 32 AF XY: 0.00950 AC XY: 707 AN XY: 74416

African (AFR) AF: 0.00279 AC: 116 AN: 41546

American (AMR) AF: 0.00765 AC: 117 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.0189 AC: 200 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0141 AC: 959 AN: 68004

Other (OTH) AF: 0.00854 AC: 18 AN: 2108

Alfa AF: 0.0135 Hom.: 5

Bravo AF: 0.00898

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 26, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tuberous sclerosis 2 Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tuberous sclerosis syndrome Other:1

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.2
DANN	Benign	0.89
PhyloP100		-0.10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

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: rs145738496; hg19: chr16-2125769; COSMIC: COSV54762828;