16-2071830-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6

The NM_000548.5(TSC2):c.1993C>G(p.Pro665Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000376 in 1,596,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P665L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 4.45

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37090868).

BP6

Variant 16-2071830-C-G is Benign according to our data. Variant chr16-2071830-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 536057.

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
TSC2	NM_000548.5	MANE Select	c.1993C>G	p.Pro665Ala	missense	Exon 19 of 42	NP_000539.2
TSC2	NM_001406663.1		c.1993C>G	p.Pro665Ala	missense	Exon 19 of 42	NP_001393592.1
TSC2	NM_001114382.3		c.1993C>G	p.Pro665Ala	missense	Exon 19 of 41	NP_001107854.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSC2	ENST00000219476.9	TSL:5 MANE Select	c.1993C>G	p.Pro665Ala	missense	Exon 19 of 42	ENSP00000219476.3
TSC2	ENST00000350773.9	TSL:1	c.1993C>G	p.Pro665Ala	missense	Exon 19 of 41	ENSP00000344383.4
TSC2	ENST00000401874.7	TSL:1	c.1993C>G	p.Pro665Ala	missense	Exon 19 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152106

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:

0.000386

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

GnomAD2 exomes

AF:

0.0000236

AC:

AN:

211494

AF XY:

0.0000258

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000309

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000277

AC:

AN:

1444820

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

717236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33096

American (AMR)

AF:

0.00

AC:

AN:

43066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25714

East Asian (EAS)

AF:

0.000103

AC:

AN:

38874

South Asian (SAS)

AF:

0.00

AC:

AN:

83442

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104488

Other (OTH)

AF:

0.00

AC:

AN:

59646

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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

AF:

0.0000131

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Uncertain:1Benign:3

Sep 19, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 07, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 12, 2024

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.

Tuberous sclerosis syndrome

Uncertain:1

Apr 10, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Benign:1

Nov 18, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.37

MetaSVM

Uncertain

0.71

MutationAssessor

Benign

1.9

PhyloP100

4.5

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.47

Sift

Benign

0.11

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.40

MutPred

0.40

Loss of glycosylation at P665 (P = 0.0214)

MVP

0.80

ClinPred

0.25

GERP RS

5.5

Varity_R

0.12

gMVP

0.52

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

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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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over