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rs147052890

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_003238.6(TGFB2):c.303G>A(p.Lys101=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,609,824 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00070 ( 3 hom., cov: 32)
Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

TGFB2
NM_003238.6 synonymous

Scores

2

Clinical Significance

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

Conservation

PhyloP100: 2.82
Variant links:
Genes affected
TGFB2 (HGNC:11768): (transforming growth factor beta 2) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. Disruption of the TGF-beta/SMAD pathway has been implicated in a variety of human cancers. A chromosomal translocation that includes this gene is associated with Peters' anomaly, a congenital defect of the anterior chamber of the eye. Mutations in this gene may be associated with Loeys-Dietz syndrome. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.36).
BP6
Variant 1-218347004-G-A is Benign according to our data. Variant chr1-218347004-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 380608.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=1}.
BP7
Synonymous conserved (PhyloP=2.82 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000696 (106/152198) while in subpopulation NFE AF= 0.000309 (21/68032). AF 95% confidence interval is 0.000207. There are 3 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
High AC in GnomAd at 106 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TGFB2NM_003238.6 linkuse as main transcriptc.303G>A p.Lys101= synonymous_variant 1/7 ENST00000366930.9
TGFB2NM_001135599.4 linkuse as main transcriptc.303G>A p.Lys101= synonymous_variant 1/8
TGFB2NR_138148.2 linkuse as main transcriptn.1669G>A non_coding_transcript_exon_variant 1/7
TGFB2NR_138149.2 linkuse as main transcriptn.1669G>A non_coding_transcript_exon_variant 1/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TGFB2ENST00000366930.9 linkuse as main transcriptc.303G>A p.Lys101= synonymous_variant 1/71 NM_003238.6 P1P61812-1
TGFB2ENST00000366929.4 linkuse as main transcriptc.303G>A p.Lys101= synonymous_variant 1/81 P61812-2
TGFB2ENST00000488793.1 linkuse as main transcript upstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.000696
AC:
106
AN:
152198
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.0899
Gnomad AMR
AF:
0.0000654
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:
0.000309
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000164
AC:
39
AN:
238272
Hom.:
0
AF XY:
0.000162
AC XY:
21
AN XY:
129432
show subpopulations
Gnomad AFR exome
AF:
0.0000675
Gnomad AMR exome
AF:
0.0000598
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000340
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000206
AC:
300
AN:
1457626
Hom.:
0
Cov.:
31
AF XY:
0.000199
AC XY:
144
AN XY:
724752
show subpopulations
Gnomad4 AFR exome
AF:
0.0000898
Gnomad4 AMR exome
AF:
0.0000454
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000259
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.000696
AC:
106
AN:
152198
Hom.:
3
Cov.:
32
AF XY:
0.000565
AC XY:
42
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000309
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000263
Hom.:
0
Bravo
AF:
0.000986

ClinVar

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

Submissions by phenotype

Loeys-Dietz syndrome 4 Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 17, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 15, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 16, 2022- -
Benign, criteria provided, single submitterclinical testingGeneDxJun 30, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 16, 2016This alteration is classified as likely benign based on a combination of the following: 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. -
Ehlers-Danlos syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenSep 17, 2020- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2023TGFB2: BP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.36
Cadd
Benign
13
Dann
Benign
0.93

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: rs147052890; hg19: chr1-218520346; API