rs35364892

chr16-2056112-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000548.5(TSC2):c.600-84C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00924 in 1,568,486 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0078 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (104 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.508

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-2056112-C-T is Benign according to our data. Variant chr16-2056112-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 49409.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2056112-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0078 (1188/152232) while in subpopulation SAS AF= 0.0187 (90/4822). AF 95% confidence interval is 0.0156. There are 10 homozygotes in gnomad4. There are 588 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1189 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.600-84C>T		intron_variant		ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.600-84C>T		intron_variant		5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.00782 AC: 1189 AN: 152116 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00760

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.00717

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00764

Gnomad OTH AF: 0.00767

GnomAD3 exomes AF: 0.00911 AC: 2183 AN: 239650 Hom.: 18 AF XY: 0.0101 AC XY: 1317 AN XY: 130608

Gnomad AFR exome AF: 0.00666

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.0369

Gnomad EAS exome AF: 0.000274

Gnomad SAS exome AF: 0.0190

Gnomad FIN exome AF: 0.00611

Gnomad NFE exome AF: 0.00808

Gnomad OTH exome AF: 0.00916

GnomAD4 exome AF: 0.00939 AC: 13299 AN: 1416254 Hom.: 104 Cov.: 26 AF XY: 0.00982 AC XY: 6946 AN XY: 707014

Gnomad4 AFR exome AF: 0.00767

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.0371

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.0195

Gnomad4 FIN exome AF: 0.00657

Gnomad4 NFE exome AF: 0.00859

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.00780 AC: 1188 AN: 152232 Hom.: 10 Cov.: 32 AF XY: 0.00790 AC XY: 588 AN XY: 74414

Gnomad4 AFR AF: 0.00756

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0187

Gnomad4 FIN AF: 0.00717

Gnomad4 NFE AF: 0.00765

Gnomad4 OTH AF: 0.00759

Alfa AF: 0.0119 Hom.: 2

Bravo AF: 0.00736

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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	-0.86
Cadd	Benign	2.3
Dann	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs35364892; hg19: chr16-2106113; COSMIC: COSV54761845; COSMIC: COSV54761845;