12-57230889-CAG-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_005412.6(SHMT2):c.121_122delAG(p.Arg41GlyfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_005412.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152120Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251418Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135912
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461862Hom.: 0 AF XY: 0.00000963 AC XY: 7AN XY: 727230
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152120Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74300
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: SHMT2 c.121_122delAG (p.Arg41GlyfsX12) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss-of-function variants in SHMT2 as causative of disease. The variant allele was found at a frequency of 2.4e-05 in 251418 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.121_122delAG in individuals affected with Neurodevelopmental Disorder With Cardiomyopathy, Spasticity, And Brain Abnormalities and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at