chr16-2056361-C-G

Position:

• chr16-2056361-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000548.5(TSC2):​c.648+117C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 1,431,116 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0048 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (44 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -1.67

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00481 (733/152290) while in subpopulation NFE AF= 0.00894 (608/68004). AF 95% confidence interval is 0.00835. There are 5 homozygotes in gnomad4. There are 342 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 733 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.648+117C>G		intron_variant		ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.648+117C>G		intron_variant		5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.00482 AC: 733 AN: 152172 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00894

Gnomad OTH AF: 0.00622

GnomAD4 exome AF: 0.00668 AC: 8546 AN: 1278826 Hom.: 44 AF XY: 0.00659 AC XY: 4218 AN XY: 639852

Gnomad4 AFR exome AF: 0.00101

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.000163

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00112

Gnomad4 FIN exome AF: 0.00330

Gnomad4 NFE exome AF: 0.00818

Gnomad4 OTH exome AF: 0.00486

GnomAD4 genome AF: 0.00481 AC: 733 AN: 152290 Hom.: 5 Cov.: 32 AF XY: 0.00459 AC XY: 342 AN XY: 74482

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00894

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00449 Hom.: 3

Bravo AF: 0.00426

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.017
DANN	Benign	0.40

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: rs45460197; hg19: chr16-2106362; COSMIC: COSV104375915; COSMIC: COSV104375915;