11-118260174-GC-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005797.4(MPZL2):βc.463delGβ(p.Ala155LeufsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_005797.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MPZL2 | NM_005797.4 | c.463delG | p.Ala155LeufsTer10 | frameshift_variant | Exon 4 of 6 | ENST00000278937.7 | NP_005788.1 | |
MPZL2 | NM_144765.3 | c.463delG | p.Ala155LeufsTer10 | frameshift_variant | Exon 4 of 5 | NP_658911.1 | ||
MPZL2 | XM_047426229.1 | c.399delG | p.Trp133CysfsTer35 | frameshift_variant | Exon 4 of 4 | XP_047282185.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MPZL2 | ENST00000278937.7 | c.463delG | p.Ala155LeufsTer10 | frameshift_variant | Exon 4 of 6 | 1 | NM_005797.4 | ENSP00000278937.2 | ||
MPZL2 | ENST00000438295.2 | c.463delG | p.Ala155LeufsTer10 | frameshift_variant | Exon 4 of 5 | 1 | ENSP00000408362.2 | |||
MPZL2 | ENST00000529376.5 | n.593delG | non_coding_transcript_exon_variant | Exon 4 of 4 | 2 | |||||
MPZL2 | ENST00000534175.6 | n.511delG | non_coding_transcript_exon_variant | Exon 3 of 5 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251100Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135706
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461746Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5AN XY: 727170
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152294Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74466
ClinVar
Submissions by phenotype
Hearing loss, autosomal recessive 111 Pathogenic:4
PM2_Supporting+PVS1+PM3+PP1 -
Individual with NSHL carried compound heterozygous variants in MPZL2. AR NSHL had a characteristic of moderate and progressive hearing loss. Hearing impairment in the individual was a sporadic case in his family. -
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Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00003, PM2_M). The variant has been reported to be associated with MPZL2 related disorder (ClinVar ID: VCV000689320, PMID:32203226, 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at