rs1555512330

Variant names:

• chr16-2081624-AACCCGCTCAGCCCTTTCTCCTCGGACATCAACAACATGCCCCTGCAGGAGCTGTCTAACGCCCTCATGGCGGCTGAGCGCTTCAAGGAGCACCGGGACACAGCCCTGTACAAGTCACTGTCGGTGCCGGCAGCCAGCACGGCCAAACCCCCTCCTCTGCCTCGCTCCAACACAGGTGAGTGGCATGGCGGGCCTTGGCACGG-A
• rs1555512330
• ENST00000439117.6:n.*2808_*2981+28del

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3 PP5_Moderate

The ENST00000439117.6(TSC2):​n.*2808_*2981+28del variant causes a splice region, non coding transcript exon change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: TSC2 ENST00000439117.6 splice_region, non_coding_transcript_exon
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.92
• 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 3 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 16-2081624-AACCCGCTCAGCCCTTTCTCCTCGGACATCAACAACATGCCCCTGCAGGAGCTGTCTAACGCCCTCATGGCGGCTGAGCGCTTCAAGGAGCACCGGGACACAGCCCTGTACAAGTCACTGTCGGTGCCGGCAGCCAGCACGGCCAAACCCCCTCCTCTGCCTCGCTCCAACACAGGTGAGTGGCATGGCGGGCCTTGGCACGG-A is Pathogenic according to our data. Variant chr16-2081624-AACCCGCTCAGCCCTTTCTCCTCGGACATCAACAACATGCCCCTGCAGGAGCTGTCTAACGCCCTCATGGCGGCTGAGCGCTTCAAGGAGCACCGGGACACAGCCCTGTACAAGTCACTGTCGGTGCCGGCAGCCAGCACGGCCAAACCCCCTCCTCTGCCTCGCTCCAACACAGGTGAGTGGCATGGCGGGCCTTGGCACGG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 535979.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000439117.6. 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.3641_3814+28del	p.Asn1214_Val1272delinsMet	splice_donor disruptive_inframe_deletion splice_region intron	Exon 31 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.3638_3811+28del	p.Asn1213_Val1271delinsMet	splice_donor disruptive_inframe_deletion splice_region intron	Exon 31 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.3641_3814+28del	p.Pro1215_Asp1272del	splice_donor conservative_inframe_deletion splice_region intron	Exon 31 of 41	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000439117.6	TSL:1	n.*2808_*2981+28del		splice_region non_coding_transcript_exon	Exon 27 of 38	ENSP00000406980.2
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.3641_3814+28del	p.Asn1214_Val1272delinsMet	splice_donor disruptive_inframe_deletion splice_region intron	Exon 31 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.3641_3814+28del	p.Pro1215_Asp1272del	splice_donor conservative_inframe_deletion splice_region intron	Exon 31 of 41	ENSP00000344383.4

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

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		9.9
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555512330; hg19: chr16-2131625;