15-23645746-TG-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_019066.5(MAGEL2):c.1996delC(p.Gln666SerfsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,421,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_019066.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000141 AC: 2AN: 1421014Hom.: 0 Cov.: 32 AF XY: 0.00000284 AC XY: 2AN XY: 703224
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This sequence change creates a premature translational stop signal (p.Gln666Serfs*36) in the MAGEL2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 584 amino acid(s) of the MAGEL2 protein. 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 premature translational stop signal has been observed in individual(s) with severe arthrogryposis and fetal akinesia (PMID: 26365340, 27195816; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 440463). This variant disrupts a region of the MAGEL2 protein in which other variant(s) (c.1996dup) have been determined to be pathogenic (PMID: 27195816). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 584 amino acids are lost and replaced with 36 incorrect amino acids; This variant is associated with the following publications: (PMID: 31680349, 31397880, 30302899, 26365340, 31152388, 27195816) -
Schaaf-Yang syndrome Pathogenic:1Other:1
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Pre- or perinatally lethal in all reported affected persons -
Multiple joint contractures;C0266362:Ambiguous genitalia;C1858120:Generalized hypotonia;C3278923:Ventriculomegaly Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at