dbSNP rs1555514052: TSC2:p.Pro1389_Glu1390insProLeuSerLysSerSerSerSerPro (chr16-2084361-A-AGCCCCTGAGCAAGTCCAGCTCCTCTCC) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_000548.5(TSC2):c.4140_4166dupGCCCCTGAGCAAGTCCAGCTCCTCTCC(p.Pro1389_Glu1390insProLeuSerLysSerSerSerSerPro) variant causes a disruptive inframe insertion change involving the alteration of a non-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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P1389P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TSC2
NM_000548.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.82

Publications

0 publications found

Variant links:

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

TSC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000548.5.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSC2	NM_000548.5	MANE Select	c.4140_4166dupGCCCCTGAGCAAGTCCAGCTCCTCTCC	p.Pro1389_Glu1390insProLeuSerLysSerSerSerSerPro	disruptive_inframe_insertion	Exon 34 of 42	NP_000539.2	P49815-1
TSC2	NM_001406663.1		c.4137_4163dupGCCCCTGAGCAAGTCCAGCTCCTCTCC	p.Pro1388_Glu1389insProLeuSerLysSerSerSerSerPro	disruptive_inframe_insertion	Exon 34 of 42	NP_001393592.1	A0A2R8Y6C9
TSC2	NM_001114382.3		c.4071_4097dupGCCCCTGAGCAAGTCCAGCTCCTCTCC	p.Pro1366_Glu1367insProLeuSerLysSerSerSerSerPro	disruptive_inframe_insertion	Exon 33 of 41	NP_001107854.1	P49815-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSC2	ENST00000219476.9	TSL:5 MANE Select	c.4140_4166dupGCCCCTGAGCAAGTCCAGCTCCTCTCC	p.Pro1389_Glu1390insProLeuSerLysSerSerSerSerPro	disruptive_inframe_insertion	Exon 34 of 42	ENSP00000219476.3	P49815-1
TSC2	ENST00000350773.9	TSL:1	c.4071_4097dupGCCCCTGAGCAAGTCCAGCTCCTCTCC	p.Pro1366_Glu1367insProLeuSerLysSerSerSerSerPro	disruptive_inframe_insertion	Exon 33 of 41	ENSP00000344383.4	P49815-4
TSC2	ENST00000401874.7	TSL:1	c.3939_3965dupGCCCCTGAGCAAGTCCAGCTCCTCTCC	p.Pro1322_Glu1323insProLeuSerLysSerSerSerSerPro	disruptive_inframe_insertion	Exon 32 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000137

AC:

AN:

1460316

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51980

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111952

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

Tuberous sclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.8

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over