rs1436552875
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PP3_StrongPP5_Very_StrongBS2
The NM_003238.6(TGFB2):c.547C>T(p.Arg183Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183H) has been classified as Uncertain significance.
Frequency
Consequence
NM_003238.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFB2 | NM_003238.6 | c.547C>T | p.Arg183Cys | missense_variant | 3/7 | ENST00000366930.9 | |
TGFB2 | NM_001135599.4 | c.631C>T | p.Arg211Cys | missense_variant | 4/8 | ||
TGFB2 | NR_138148.2 | n.1913C>T | non_coding_transcript_exon_variant | 3/7 | |||
TGFB2 | NR_138149.2 | n.1997C>T | non_coding_transcript_exon_variant | 4/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFB2 | ENST00000366930.9 | c.547C>T | p.Arg183Cys | missense_variant | 3/7 | 1 | NM_003238.6 | P1 | |
TGFB2 | ENST00000366929.4 | c.631C>T | p.Arg211Cys | missense_variant | 4/8 | 1 | |||
TGFB2 | ENST00000488793.1 | n.211C>T | non_coding_transcript_exon_variant | 3/3 | 3 | ||||
TGFB2 | ENST00000479322.1 | upstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727234
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74350
ClinVar
Submissions by phenotype
Loeys-Dietz syndrome 4 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 09, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 183 of the TGFB2 protein (p.Arg183Cys). This variant is present in population databases (no rsID available, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of TGFB2-related conditions (PMID: 32897753; Invitae). This variant is also known as p.Arg211Cys. ClinVar contains an entry for this variant (Variation ID: 547806). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TGFB2 protein function. This variant disrupts the p.Arg183 amino acid residue in TGFB2. Other variant(s) that disrupt this residue have been observed in individuals with TGFB2-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at