rs886045026
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_013296.5(GPSM2):βc.1473delβ(p.Phe492SerfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,459,718 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
Genomes: π 0.000026 ( 0 hom., cov: 32)
Exomes π: 0.000014 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
GPSM2
NM_013296.5 frameshift
NM_013296.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.60
Genes affected
GPSM2 (HGNC:29501): (G protein signaling modulator 2) The protein encoded by this gene belongs to a family of proteins that modulate activation of G proteins, which transduce extracellular signals received by cell surface receptors into integrated cellular responses. The N-terminal half of this protein contains 10 copies of leu-gly-asn (LGN) repeat, and the C-terminal half contains 4 GoLoco motifs, which are involved in guanine nucleotide exchange. This protein may play a role in neuroblast division and in the development of normal hearing. Mutations in this gene are associated with autosomal recessive nonsyndromic deafness (DFNB82). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]
AKNAD1 (HGNC:28398): (AKNA domain containing 1) This gene encodes a protein which contains a domain found in an AT-hook-containing transcription factor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2012]
CLCC1 (HGNC:29675): (chloride channel CLIC like 1) Predicted to enable chloride channel activity. Predicted to be involved in chloride transport. Located in endoplasmic reticulum and mitochondria-associated endoplasmic reticulum membrane. Implicated in retinitis pigmentosa 32. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 1-108922446-AG-A is Pathogenic according to our data. Variant chr1-108922446-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 291707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-108922446-AG-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GPSM2 | NM_013296.5 | c.1473del | p.Phe492SerfsTer5 | frameshift_variant | 13/15 | ENST00000264126.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GPSM2 | ENST00000264126.9 | c.1473del | p.Phe492SerfsTer5 | frameshift_variant | 13/15 | 1 | NM_013296.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 4AN: 152218Hom.: 0 Cov.: 32 FAILED QC
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251354Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135860
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1459718Hom.: 0 Cov.: 29 AF XY: 0.0000124 AC XY: 9AN XY: 726352
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.0000263 AC: 4AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74374
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 30, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23208854, 22578326, 27180139, 23494849, 32445360, 28555434) - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 06, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 291707). This premature translational stop signal has been observed in individual(s) with hearing loss (PMID: 23208854). 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 creates a premature translational stop signal (p.Phe492Serfs*5) in the GPSM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GPSM2 are known to be pathogenic (PMID: 22578326, 22987632). - |
Chudley-McCullough syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 08, 2012 | - - |
GPSM2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The GPSM2 c.1473delG (p.Phe492SerfsTer5) variant, also referred to as c.1471delG, results in a frameshift and is predicted to cause a premature truncation of the protein. The p.Phe492SerfsTer5 variant has been reported in three studies in which it is found in a homozygous state in a total of nine patients with GPSM2-related disorders, including in eight individuals (including two sibling pairs) with Chudley-McCullough syndrome (CMS), and in one individual with a recessive form of nonsyndromic hearing loss (Doherty et al. 2012; Schrauwen et al. 2013; Almomani et al. 2013). The p.Phe492SerfsTer5 variant was absent from a single control and is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium, though this is based on only two alleles so it is presumed to be rare. Due to the potential impact of frameshift variants and supporting evidence from the literature, this variant is classified as pathogenic for GPSM2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 09, 2016 | The p.Phe492fs variant in GPSM2 has been previously reported in 6 homozygous ind ividuals with Chudley McCullough syndrome (CMS) and 1 homozygous individual with sensorineural hearing loss, and it segregated in two affected siblings (Almoman i 2013, Doherty 2012, Hendriks 1999, Schrauwen 2013). CMS is characterized by s ensorineural hearing loss, typically in the severe to profound range, with chara cteristic abnormalities on brain MRI. Despite the brain abnormalities found on i maging, individuals with CMS do not typically have cognitive or developmental ab normalities. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 492 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted t o lead to a truncated or absent protein. In summary, this variant meets our crit eria to be classified as pathogenic for Chudley McCullough syndrome in an autoso mal recessive manner based on the predicted impact of the variant and previously reported affected individuals. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at