rs1262967003

Variant names:

• chr16-2086871-GGTGA-G
• rs1262967003
• NM_000548.5:c.4989+6_4989+9delTGAG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The NM_000548.5(TSC2):​c.4989+6_4989+9delTGAG variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000442 in 1,583,178 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: TSC2 NM_000548.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 9.83
• 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 16-2086871-GGTGA-G is Benign according to our data. Variant chr16-2086871-GGTGA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 536094.

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.4989+6_4989+9delTGAG		splice_region intron	N/A	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.4986+6_4986+9delTGAG		splice_region intron	N/A	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.4920+6_4920+9delTGAG		splice_region intron	N/A	NP_001107854.1	P49815-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.4989+6_4989+9delTGAG		splice_region intron	N/A	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.4920+6_4920+9delTGAG		splice_region intron	N/A	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.4788+6_4788+9delTGAG		splice_region intron	N/A	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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 AF: 0.00000419 AC: 6 AN: 1430932 Hom.: 0 AF XY: 0.00000282 AC XY: 2 AN XY: 709534

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32674

American (AMR) AF: 0.00 AC: 0 AN: 40198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25592

East Asian (EAS) AF: 0.0000265 AC: 1 AN: 37716

South Asian (SAS) AF: 0.00 AC: 0 AN: 82634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4958

European-Non Finnish (NFE) AF: 0.00000455 AC: 5 AN: 1097944

Other (OTH) AF: 0.00 AC: 0 AN: 59244

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000000318634), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74382

African (AFR) AF: 0.0000241 AC: 1 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Tuberous sclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.46		Position offset: -29

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

Other links and lift over

dbSNP: rs1262967003; hg19: chr16-2136872;