rs138262219
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The ENST00000359013.4(TGFBR2):c.166C>A(p.His56Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
ENST00000359013.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFBR2 | NM_003242.6 | c.94+16293C>A | intron_variant | ENST00000295754.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFBR2 | ENST00000359013.4 | c.166C>A | p.His56Asn | missense_variant | 2/8 | 1 | |||
TGFBR2 | ENST00000295754.10 | c.94+16293C>A | intron_variant | 1 | NM_003242.6 | P1 | |||
TGFBR2 | ENST00000673250.1 | n.215C>A | non_coding_transcript_exon_variant | 2/4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000522 AC: 13AN: 248890Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134742
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461642Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12AN XY: 727122
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2023 | At the protein level, in silico analysis supports that this missense variant does not alter protein structure/function; At the mRNA level, in silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported using an alternate transcript of the gene; This variant is associated with the following publications: (PMID: 23099432) - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 07, 2021 | The TGFBR2 c.166C>A; p.His56Asn variant (rs138262219), has been reported in the literature in one Ashkenazi Jewish patient with thoracic aortopathy and in his affected son. However, functional tests conducted in fibroblasts from this individual and in a rat cell culture model demonstrated conflicting effects of this variant on downstream TGFBR2 signaling and functioning (Bee 2012). This variant is reported in the ClinVar database (Variation ID: 213913) and is found in the Ashkenazi Jewish population with an allele frequency of 0.1 % (11/10,068 alleles) in the Genome Aggregation Database. The histidine at codon 56 is weakly conserved and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.188). Due to limited information, the clinical significance of the p.His56Asn variant is uncertain at this time. REFERENCES Bee KJ et al CJ. TGFBRIIb mutations trigger aortic aneurysm pathogenesis by altering transforming growth factor B2 signal transduction. Circ Cardiovasc Genet. 2012 Dec;5(6):621-9. PMID: 23099432. - |
Malignant tumor of esophagus;C1860896:Colorectal cancer, hereditary nonpolyposis, type 6;C2674574:Loeys-Dietz syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 09, 2022 | - - |
Diabetic retinopathy Other:1
Uncertain risk allele, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Potent mutations in TGFBR2 gene encodes the transforming growth factor that have been associated with angiogenesis and diabetic retinopathy. More clinical studies are needed for stronger association. However, more evidence is required to confer the association of this particular variant rs138262219 with diabetic retinopathy. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at