rs145738496

Positions:

• chr16-2075768-G-A
• chr16-2075768-G-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 65156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2075768-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1488 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.2546-31G>A		intron_variant		ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.2546-31G>A		intron_variant		5	NM_000548.5	ENSP00000219476.3

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

GnomAD3 exomes AF: 0.0105 AC: 2594 AN: 246860 Hom.: 23 AF XY: 0.0103 AC XY: 1388 AN XY: 134470

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 SAS exome AF: 0.00173

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

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.00445

Gnomad4 ASJ exome AF: 0.0153

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00226

Gnomad4 FIN exome AF: 0.0229

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.00959

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

Gnomad4 AFR AF: 0.00279

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0189

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.00854

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

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Tuberous sclerosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.2
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

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