16-2048067-TAAGTGGCGGTCCCCACGGGGC-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000548.5(TSC2):c.-30+25_-30+45del variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,426,560 control chromosomes in the GnomAD database, including 22 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (11 hom.)
• Consequence: TSC2 NM_000548.5 splice_donor_5th_base, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.421

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 -16 ACMG points.

• BP6: Variant 16-2048067-TAAGTGGCGGTCCCCACGGGGC-T is Benign according to our data. Variant chr16-2048067-TAAGTGGCGGTCCCCACGGGGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 670053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2048067-TAAGTGGCGGTCCCCACGGGGC-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00526 (800/152008) while in subpopulation AFR AF= 0.0176 (731/41472). AF 95% confidence interval is 0.0166. There are 11 homozygotes in gnomad4. There are 379 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 800 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.-30+25_-30+45del		splice_donor_5th_base_variant, intron_variant		ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.-30+25_-30+45del		splice_donor_5th_base_variant, intron_variant		5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 800 AN: 151898 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00330

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00622

GnomAD4 exome AF: 0.00102 AC: 1301 AN: 1274552 Hom.: 11 AF XY: 0.00100 AC XY: 621 AN XY: 619840

Gnomad4 AFR exome AF: 0.0194

Gnomad4 AMR exome AF: 0.000941

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0114

Gnomad4 SAS exome AF: 0.000437

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000332

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00526 AC: 800 AN: 152008 Hom.: 11 Cov.: 32 AF XY: 0.00510 AC XY: 379 AN XY: 74296

Gnomad4 AFR AF: 0.0176

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00331

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00367 Hom.: 0

Bravo AF: 0.00585

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 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. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Oct 09, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs565651015; hg19: chr16-2098068;