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GeneBe

16-2072923-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_000548.5(TSC2):c.2295C>T(p.Ala765=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,618 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). Synonymous variant affecting the same amino acid position (i.e. A765A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

TSC2
NM_000548.5 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6O:1

Conservation

PhyloP100: -3.58
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 -10 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.74).
BP6
Variant 16-2072923-C-T is Benign according to our data. Variant chr16-2072923-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 49677.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=1, Benign=4, Uncertain_significance=1}. Variant chr16-2072923-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-3.58 with no splicing effect.
BS2
High AC in GnomAd at 29 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TSC2NM_000548.5 linkuse as main transcriptc.2295C>T p.Ala765= synonymous_variant 21/42 ENST00000219476.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TSC2ENST00000219476.9 linkuse as main transcriptc.2295C>T p.Ala765= synonymous_variant 21/425 NM_000548.5 P49815-1

Frequencies

GnomAD3 genomes
AF:
0.000191
AC:
29
AN:
152224
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000651
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000558
AC:
14
AN:
251056
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135844
show subpopulations
Gnomad AFR exome
AF:
0.000678
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000301
AC:
44
AN:
1461276
Hom.:
0
Cov.:
31
AF XY:
0.0000316
AC XY:
23
AN XY:
726910
show subpopulations
Gnomad4 AFR exome
AF:
0.000986
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000629
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.000190
AC:
29
AN:
152342
Hom.:
0
Cov.:
33
AF XY:
0.000107
AC XY:
8
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.000649
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000508
Hom.:
0
Bravo
AF:
0.000155
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 06, 2018- -
Benign, criteria provided, single submitterclinical testingGeneDxAug 09, 2021- -
Tuberous sclerosis 2 Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 30, 2024- -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submittercurationSema4, Sema4Feb 07, 2022- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 19, 2016This 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. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 11, 2022- -
Tuberous sclerosis syndrome Other:1
not provided, no classification providedcurationTuberous sclerosis database (TSC2)-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.74
Cadd
Benign
0.20
Dann
Benign
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs45509500; hg19: chr16-2122924; API