16-2055054-A-C

Variant names:

• chr16-2055054-A-C
• rs2073636
• NM_000548.5:c.482-348A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000548.5(TSC2):​c.482-348A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 152,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000044 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.236
• Publications: 24 publications found

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 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000204 (31/152016) while in subpopulation AFR AF = 0.000723 (30/41508). AF 95% confidence interval is 0.000519. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.482-348A>C		intron_variant	Intron 5 of 41	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.482-348A>C		intron_variant	Intron 5 of 41	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.000198 AC: 30 AN: 151898 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000701

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000437 AC: 11 AN: 251852 Hom.: 1 Cov.: 0 AF XY: 0.0000372 AC XY: 5 AN XY: 134430

African (AFR) AF: 0.00124 AC: 9 AN: 7246

American (AMR) AF: 0.00 AC: 0 AN: 12312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7012

East Asian (EAS) AF: 0.00 AC: 0 AN: 13090

South Asian (SAS) AF: 0.00 AC: 0 AN: 41756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 964

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 144236

Other (OTH) AF: 0.000148 AC: 2 AN: 13472

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152016 Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 15 AN XY: 74294

African (AFR) AF: 0.000723 AC: 30 AN: 41508

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67940

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 53598

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.73
DANN	Benign	0.33
PhyloP100		-0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2073636; hg19: chr16-2105055;