rs1555499625

Variant names:

• chr16-2058739-AC-A
• rs1555499625
• NM_000548.5:c.849-7delC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The ENST00000219476.9(TSC2):​c.849-7delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,423,846 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSC2 ENST00000219476.9 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.570
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 16-2058739-AC-A is Benign according to our data. Variant chr16-2058739-AC-A is described in ClinVar as Likely_benign. ClinVar VariationId is 468189.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000219476.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.849-7delC		splice_region intron	N/A	NP_000539.2
	TSC2	NM_001406663.1		c.849-7delC		splice_region intron	N/A	NP_001393592.1
	TSC2	NM_001114382.3		c.849-7delC		splice_region intron	N/A	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.849-7delC		splice_region intron	N/A	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.849-7delC		splice_region intron	N/A	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.849-7delC		splice_region intron	N/A	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1423846 Hom.: 0 Cov.: 32 AF XY: 0.00000142 AC XY: 1 AN XY: 704594

African (AFR) AF: 0.00 AC: 0 AN: 32948

American (AMR) AF: 0.00 AC: 0 AN: 38650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25384

East Asian (EAS) AF: 0.00 AC: 0 AN: 38366

South Asian (SAS) AF: 0.00 AC: 0 AN: 81378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4904

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092728

Other (OTH) AF: 0.0000339 AC: 2 AN: 58928

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Tuberous sclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.57

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: rs1555499625; hg19: chr16-2108740;