NM_000548.5:c.2220+32delG

Variant names:

• chr16-2072390-TG-T
• rs137854354
• NM_000548.5:c.2220+32delG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000548.5(TSC2):​c.2220+32delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00338 in 1,612,866 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (19 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -3.26
• Publications: 0 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: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• lymphangioleiomyomatosis

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0028 (426/152168) while in subpopulation SAS AF = 0.00953 (46/4826). AF 95% confidence interval is 0.00734. There are 2 homozygotes in GnomAd4. There are 227 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 426 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.2220+32delG		intron	N/A	NP_000539.2
	TSC2	NM_001406663.1		c.2220+32delG		intron	N/A	NP_001393592.1
	TSC2	NM_001114382.3		c.2220+32delG		intron	N/A	NP_001107854.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.2220+28delG		intron	N/A	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.2220+28delG		intron	N/A	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.2220+28delG		intron	N/A	ENSP00000384468.2

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 426 AN: 152050 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.00867

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00952

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00350 AC: 874 AN: 249924 AF XY: 0.00394

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00365

Gnomad ASJ exome AF: 0.00648

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00210

Gnomad NFE exome AF: 0.00287

Gnomad OTH exome AF: 0.00508

GnomAD4 exome AF: 0.00344 AC: 5026 AN: 1460698 Hom.: 19 Cov.: 32 AF XY: 0.00372 AC XY: 2705 AN XY: 726500

African (AFR) AF: 0.000538 AC: 18 AN: 33464

American (AMR) AF: 0.00335 AC: 150 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00839 AC: 219 AN: 26114

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39662

South Asian (SAS) AF: 0.00958 AC: 826 AN: 86250

European-Finnish (FIN) AF: 0.00181 AC: 96 AN: 52972

Middle Eastern (MID) AF: 0.00729 AC: 42 AN: 5764

European-Non Finnish (NFE) AF: 0.00308 AC: 3418 AN: 1111408

Other (OTH) AF: 0.00423 AC: 255 AN: 60354

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152168 Hom.: 2 Cov.: 33 AF XY: 0.00305 AC XY: 227 AN XY: 74394

African (AFR) AF: 0.000506 AC: 21 AN: 41538

American (AMR) AF: 0.00556 AC: 85 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00867 AC: 30 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00953 AC: 46 AN: 4826

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00330 AC: 224 AN: 67968

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.00309 Hom.: 0

Bravo AF: 0.00281

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs137854354; hg19: chr16-2122391;