rs145226920
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002180.3(IGHMBP2):c.1488C>A(p.Cys496*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,606,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_002180.3 stop_gained
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/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
IGHMBP2 | NM_002180.3 | c.1488C>A | p.Cys496* | stop_gained | 10/15 | ENST00000255078.8 | NP_002171.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IGHMBP2 | ENST00000255078.8 | c.1488C>A | p.Cys496* | stop_gained | 10/15 | 1 | NM_002180.3 | ENSP00000255078.4 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152138Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000158 AC: 37AN: 233468Hom.: 0 AF XY: 0.000166 AC XY: 21AN XY: 126560
GnomAD4 exome AF: 0.000372 AC: 541AN: 1454036Hom.: 0 Cov.: 31 AF XY: 0.000376 AC XY: 272AN XY: 722552
GnomAD4 genome AF: 0.000118 AC: 18AN: 152256Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6AN XY: 74430
ClinVar
Submissions by phenotype
not provided Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 02, 2017 | The p.Cys496Ter variant has been reported in homozygous form as well as in compound heterozygous form together with missense or other nonsense variants in infants with spinal muscular atrophy with respiratory distress type 1 (SMARD1) with age onset of respiratory distress ranging from 3 - 91 days after birth (Grohmann 2003). Many affected infants presented with intrauterine growth restriction, decreased fetal movements, weak cry, congenital foot deformities due to early involvement of distal muscles of the lower limbs, eventration of the diaphragm due to a diaphragmatic paralysis, involvement of the autonomic nervous system, neurogenic changes in electromyography, decrease in motor nerve conduction velocity and absence of motor response after maximum stimulation, as well as fiber hypertrophy and atrophy on muscle biopsy (Grohmann 2003). Furthermore, Maystad et al. (2004) reported an infant who presented at 2 months with muscular weakness, at 2.5 month with respiratory distress and who died at 6 months. He carried the same p.Cys496Ter variant but a second IGHMBP2 variant was not identified (Maystad 2004). Additionally, Litvinenko et al. (2014) reported two infant siblings with p.Cys496Ter and Gln260fs compound heterozygous variants with severe spinal muscular atrophy respiratory distress 1, persistent eventration of the right hemidiaphragm, hypotonia due to hypo- and areflexia, complete paralysis of the limbs and mild contractures, electromyography showing active denervation, and total absence of IGHMBP2 enzyme activity. Finally, Cottenie et al. (2014) reported a 15 year old male with foot drop (first presenting at age 4), limb weakness, and ankle foot orthoses, who carried p.Cys496Ter and a missense variant. - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 16, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 07, 2024 | Nonsense 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; This variant is associated with the following publications: (PMID: 23449687, 25439726, 15108294, 25525159, 29431110, 26709713, 31827005, 31589614, 33442022, 32573669, 32376792, 34726235, 31345219, 14681881) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 15, 2024 | PM2, PM3, PS4_moderate, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 26, 2015 | - - |
Autosomal recessive distal spinal muscular atrophy 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Aug 18, 2015 | This variant has been previously reported as disease-causing and was identified in trans with a predicted pathogenic variant in an individual with congenital hypotonia. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth disease, axonal, type 2S (MIM#616155), and distal hereditary motor neuronopathy, type VI (MIM#604320). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (42 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic in individuals with either spinal muscular atrophy with respiratory distress (SMARD) or Charcot-Marie-Tooth (CMT) (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in both compound heterozygous and homozygous individuals with SMARD, and rarely in individuals with CMT (ClinVar, PMID: 25439726, PMID: 30598237). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 23, 2024 | This sequence change creates a premature translational stop signal (p.Cys496*) in the IGHMBP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IGHMBP2 are known to be pathogenic (PMID: 14681881, 25439726, 25568292). This variant is present in population databases (rs145226920, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with spinal muscular atrophy with respiratory distress 1 (SMARD1) (PMID: 14506069, 14681881, 19157874, 23449687, 26257172). ClinVar contains an entry for this variant (Variation ID: 234316). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | The IGHMBP2 c.1488C>A (p.C496*) nonsense variant is predicted to result in an absent or aberrant protein. This variant has been observed in the compound heterozygous state in individuals with Charcot-Marie-Tooth disease type 2S or spinal muscular atrophy with respiratory distress type 1 (SMARD1) (PMID: 14506069; 15108294; 19157874; 23449687; 25439726). - |
Charcot-Marie-Tooth disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
IGHMBP2-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 19, 2024 | The IGHMBP2 c.1488C>A variant is predicted to result in premature protein termination (p.Cys496*). This variant has been documented in several unrelated individuals, in the homozygous or compound heterozygous state, to be causative for autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1; Grohmann et al. 2003. PubMed ID: 14681881; Pitt et al. 2003. PubMed ID: 14506069; Litvinenko et al. 2014. PubMed ID: 23449687). The c.1488C>T (p.Cys496*) variant was also identified in an infant presenting with muscular weakness and severe respiratory distress (Maystadt et al. 2004. PubMed ID: 15108294). In addition, this variant has been reported in the compound heterozygous state in one patient with Charcot-Marie Tooth type 2 (Cottenie et al. 2014. PubMed ID: 25439726). In summary, the c.1488C>T (p.Cys496*) variant is classified as pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 23, 2020 | The p.C496* pathogenic mutation (also known as c.1488C>A), located in coding exon 10 of the IGHMBP2 gene, results from a C to A substitution at nucleotide position 1488. This changes the amino acid from a cysteine to a stop codon within coding exon 10. This alteration has been detected in the homozygous and compound heterozygous states in patients with spinal muscular atrophy with respiratory distress type 1 (SMARD1) (Grohmann K et al. Ann. Neurol., 2003 Dec;54:719-24; Joseph S et al. Neuromuscul. Disord., 2009 Mar;19:193-5; Pitt M et al. Brain, 2003 Dec;126:2682-92; San Millan B et al. Clin. Neuropathol.;35:58-65). This alteration has also been detected in the compound heterozygous state in a patient with Charcot-Marie-Tooth disease, type 2 (Cottenie E et al. Am. J. Hum. Genet., 2014 Nov;95:590-601). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Neurodevelopmental disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Jun 14, 2022 | - - |
Charcot-Marie-Tooth disease axonal type 2S Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 24, 2018 | Variant summary: IGHMBP2 c.1488C>A (p.Cys496X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00015 in 259950 control chromosomes (gnomAD). The variant, c.1488C>A, has been reported in the literature in one compound heterozygote affected with Charcot-Marie-Tooth disease type 2B2 (CMT2) (Cottenie_2014) and more frequently in compound heterozygotes and homozygotes affected with spinal muscular atrophy with respiratory distress type 1 (SMARD1)( Grohmann_2003). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic for CMT2. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at