rs565502802
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_003242.6(TGFBR2):c.4G>T(p.Gly2Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,560,118 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).
Frequency
Consequence
NM_003242.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000223 AC: 34AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000478 AC: 9AN: 188412Hom.: 0 AF XY: 0.0000388 AC XY: 4AN XY: 103100
GnomAD4 exome AF: 0.0000185 AC: 26AN: 1407800Hom.: 0 Cov.: 31 AF XY: 0.0000101 AC XY: 7AN XY: 695838
GnomAD4 genome AF: 0.000217 AC: 33AN: 152318Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17AN XY: 74470
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1Benign:2
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The p.G2C variant (also known as c.4G>T), located in coding exon 1 of the TGFBR2 gene, results from a G to T substitution at nucleotide position 4. The glycine at codon 2 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Diabetic retinopathy Pathogenic:1
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 rs565502802 with diabetic retinopathy. -
not provided Uncertain:1
Identified in a patient with features of a connective tissue disorder who harbored several other cardiogenetic variants (PMID: 35918752); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35918752, 35903967) -
not specified Benign:1
Variant summary: TGFBR2 c.4G>T (p.Gly2Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.9e-05 in 219764 control chromosomes, predominantly at a frequency of 0.00064 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 205 fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFBR2 causing Loeys-Dietz Syndrome phenotype (3.1e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.4G>T in individuals affected with Loeys-Dietz Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Loeys-Dietz syndrome 2 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at