rs727505300
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_013296.5(GPSM2):c.459_460del(p.Ala154GlnfsTer32) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. H153H) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_013296.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GPSM2 | NM_013296.5 | c.459_460del | p.Ala154GlnfsTer32 | frameshift_variant | 5/15 | ENST00000264126.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GPSM2 | ENST00000264126.9 | c.459_460del | p.Ala154GlnfsTer32 | frameshift_variant | 5/15 | 1 | NM_013296.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251442Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135886
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461654Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727146
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 09, 2019 | The p.Ala154GlnfsX32 variant in GPSM2 has not been previously identified in individuals with hearing loss or Chudley-McCullough syndrome, but has been identified in 1/251442 of the total chromosomes in gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 154 and leads to a premature termination codon 32 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function variants in the GPSM2 gene have been strongly associated with Chudley-McCullough syndrome, which is an autosomal recessive syndrome characterized by sensorineural hearing loss and specific brain malformations, without additional significant neurological or developmental abnormalities (Doherty 2012). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Chudley-McCullough syndrome. ACMG/AMP Criteria applied: PVS1, PM2. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at