rs397514957

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_000548.5(TSC2):​c.704G>A​(p.Ser235Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,612,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

5
14

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 3.18
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1745789).
BP6
Variant 16-2056699-G-A is Benign according to our data. Variant chr16-2056699-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 64942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2056699-G-A is described in Lovd as [Likely_benign]. Variant chr16-2056699-G-A is described in Lovd as [Benign].
BS2
High AC in GnomAdExome4 at 34 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TSC2NM_000548.5 linkuse as main transcriptc.704G>A p.Ser235Asn missense_variant 8/42 ENST00000219476.9 NP_000539.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TSC2ENST00000219476.9 linkuse as main transcriptc.704G>A p.Ser235Asn missense_variant 8/425 NM_000548.5 ENSP00000219476 P49815-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152230
Hom.:
0
Cov.:
32
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000400
AC:
10
AN:
250292
Hom.:
0
AF XY:
0.0000591
AC XY:
8
AN XY:
135412
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000196
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000233
AC:
34
AN:
1460234
Hom.:
0
Cov.:
32
AF XY:
0.0000289
AC XY:
21
AN XY:
726540
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000255
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000629
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152230
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000247
AC:
3
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Tuberous sclerosis 2 Benign:4
Likely benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Benign, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Jun 05, 2024This variant is considered benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 18, 2023- -
Tuberous sclerosis syndrome Benign:1Other:1
Likely benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthFeb 22, 2024- -
not provided, no classification providedcurationTuberous sclerosis database (TSC2)-- -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 13, 2017This 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 v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.13
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.62
D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Benign
-0.020
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.78
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP
Benign
0.045
D
MetaRNN
Benign
0.17
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.40
T
MutationAssessor
Benign
1.5
L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-2.3
N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL
Uncertain
0.39
Sift
Benign
0.036
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G
Benign
0.062
T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen
0.0010
B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4
0.46
MutPred
0.44
Gain of catalytic residue at S235 (P = 0.0837);Gain of catalytic residue at S235 (P = 0.0837);Gain of catalytic residue at S235 (P = 0.0837);.;Gain of catalytic residue at S235 (P = 0.0837);Gain of catalytic residue at S235 (P = 0.0837);Gain of catalytic residue at S235 (P = 0.0837);Gain of catalytic residue at S235 (P = 0.0837);.;Gain of catalytic residue at S235 (P = 0.0837);Gain of catalytic residue at S235 (P = 0.0837);Gain of catalytic residue at S235 (P = 0.0837);Gain of catalytic residue at S235 (P = 0.0837);Gain of catalytic residue at S235 (P = 0.0837);.;
MVP
0.92
ClinPred
0.10
T
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.19
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397514957; hg19: chr16-2106700; API