chr13-23805948-A-C
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_005932.4(MIPEP):c.1848+2T>G variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,400 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 Likely pathogenic (★★).
Frequency
Consequence
NM_005932.4 splice_donor
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MIPEP | NM_005932.4 | c.1848+2T>G | splice_donor_variant | ENST00000382172.4 | |||
MIPEP | XM_011535097.3 | c.1662+2T>G | splice_donor_variant | ||||
MIPEP | XM_011535098.4 | c.1848+2T>G | splice_donor_variant | ||||
MIPEP | XM_047430368.1 | c.1662+2T>G | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MIPEP | ENST00000382172.4 | c.1848+2T>G | splice_donor_variant | 1 | NM_005932.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251062Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135696
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461188Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7AN XY: 726828
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74364
ClinVar
Submissions by phenotype
Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 04, 2023 | Variant summary: MIPEP c.1848+2T>G is located in a canonical splice-site 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 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251062 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1848+2T>G in individuals affected with Lethal Left Ventricular Non-Compaction Delay Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 25, 2023 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with MIPEP-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 16 of the MIPEP gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MIPEP are known to be pathogenic (PMID: 27799064, 34620555). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at