rs1555506028

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000548.5(TSC2):c.1990T>C(p.Ser664Pro) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S664F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000071 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.43

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: 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

TSC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.791

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.1990T>C	p.Ser664Pro	missense_variant	Exon 19 of 42	ENST00000219476.9	NP_000539.2	P49815-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 link	c.1990T>C	p.Ser664Pro	missense_variant	Exon 19 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.00000706

AC:

AN:

141574

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000112

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1444134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716990

African (AFR)

AF:

0.00

AC:

AN:

33086

American (AMR)

AF:

0.00

AC:

AN:

43288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25710

East Asian (EAS)

AF:

0.00

AC:

AN:

38998

South Asian (SAS)

AF:

0.00

AC:

AN:

83476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50870

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4430

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104744

Other (OTH)

AF:

0.00

AC:

AN:

59532

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000706

AC:

AN:

141574

Hom.:

Cov.:

AF XY:

0.0000146

AC XY:

AN XY:

68398

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

36170

American (AMR)

AF:

0.00

AC:

AN:

14314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3386

East Asian (EAS)

AF:

0.00

AC:

AN:

4816

South Asian (SAS)

AF:

0.00

AC:

AN:

4520

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

8904

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66332

Other (OTH)

AF:

0.00

AC:

AN:

1968

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

D;.;.;.;.;.;.;.;.;.;.;.;D;.;D

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.79

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.4

M;.;.;.;M;M;.;.;.;M;.;M;.;.;.

PhyloP100

7.4

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.4

N;.;.;D;.;N;.;.;D;N;.;.;.;.;N

REVEL

Uncertain

0.63

Sift

Benign

0.15

T;.;.;T;.;T;.;.;T;T;.;.;.;.;T

Sift4G

Pathogenic

0.0

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

Polyphen

0.99

D;.;.;.;D;D;.;.;D;D;.;.;.;.;.

Vest4

0.58

MutPred

0.33

Loss of phosphorylation at S664 (P = 0.0069);Loss of phosphorylation at S664 (P = 0.0069);Loss of phosphorylation at S664 (P = 0.0069);.;Loss of phosphorylation at S664 (P = 0.0069);Loss of phosphorylation at S664 (P = 0.0069);Loss of phosphorylation at S664 (P = 0.0069);Loss of phosphorylation at S664 (P = 0.0069);.;Loss of phosphorylation at S664 (P = 0.0069);Loss of phosphorylation at S664 (P = 0.0069);Loss of phosphorylation at S664 (P = 0.0069);Loss of phosphorylation at S664 (P = 0.0069);Loss of phosphorylation at S664 (P = 0.0069);.;

MVP

0.87

ClinPred

0.92

GERP RS

5.5

Varity_R

0.40

gMVP

0.59

Mutation Taster

=33/67

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over