chr22-36467918-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_012473.4(TXN2):c.388-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_012473.4 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TXN2 | NM_012473.4 | c.388-1G>A | splice_acceptor_variant | ENST00000216185.7 | |||
TXN2 | XM_006724226.2 | c.388-1G>A | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TXN2 | ENST00000216185.7 | c.388-1G>A | splice_acceptor_variant | 1 | NM_012473.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249026Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134810
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461554Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727118
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74362
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 20, 2023 | Variant summary: TXN2 c.388-1G>A is located in a canonical splice-site in the last intron, and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site, and two predict the variant creates a cryptic 3' acceptor site 1nt downstream into exon 4. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 249026 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.388-1G>A in individuals affected with Combined Oxidative Phosphorylation Deficiency 29 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 after 2014. 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