chr16-2062618-G-C

Position:

• chr16-2062618-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.1361+18G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000626 in 1,589,900 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (3 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.108

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-2062618-G-C is Benign according to our data. Variant chr16-2062618-G-C is described in ClinVar as [Benign]. Clinvar id is 137738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062618-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00344 (524/152346) while in subpopulation AFR AF= 0.0122 (506/41576). AF 95% confidence interval is 0.0113. There are 3 homozygotes in gnomad4. There are 238 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 524 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1361+18G>C		intron_variant		ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1361+18G>C		intron_variant		5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.00345 AC: 525 AN: 152228 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000824 AC: 175 AN: 212336 Hom.: 0 AF XY: 0.000490 AC XY: 56 AN XY: 114402

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.000484

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000218

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.000328 AC: 471 AN: 1437554 Hom.: 3 Cov.: 30 AF XY: 0.000282 AC XY: 201 AN XY: 712916

Gnomad4 AFR exome AF: 0.0120

Gnomad4 AMR exome AF: 0.000477

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000637

Gnomad4 OTH exome AF: 0.000741

GnomAD4 genome AF: 0.00344 AC: 524 AN: 152346 Hom.: 3 Cov.: 33 AF XY: 0.00319 AC XY: 238 AN XY: 74494

Gnomad4 AFR AF: 0.0122

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.00400

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	TSC2: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.51
DANN	Benign	0.34

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: rs140223009; hg19: chr16-2112619; COSMIC: COSV104375873; COSMIC: COSV104375873;