rs746581714
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002180.3(IGHMBP2):c.983_987delAAGAA(p.Lys328ThrfsTer46) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000316 in 1,613,684 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_002180.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251488Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135920
GnomAD4 exome AF: 0.0000322 AC: 47AN: 1461502Hom.: 0 AF XY: 0.0000289 AC XY: 21AN XY: 727102
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74352
ClinVar
Submissions by phenotype
Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S Pathogenic:2
This sequence change creates a premature translational stop signal (p.Lys328Thrfs*46) 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 (rs746581714, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy with respiratory distress (SMARD1) (PMID: 14681881, 27450922). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217449). For these reasons, this variant has been classified as Pathogenic. -
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IGHMBP2-related disorder Pathogenic:1
This frameshifting variant in exon 7 of 15 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous, homozygous, and compound heterozygous change in patients with sensorimotor axonal neuropathy/ infantile spinal muscular atrophy with or without respiratory failure (PMID: 27450922, 14681881). Loss-of-function variation in IGHMBP2 is an established mechanism of disease (PMID: 14681881, 25439726, 25568292). The c.983_987del (p.Lys328ThrfsTer46) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/282884) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.983_987del (p.Lys328ThrfsTer46) variant is classified as Likely Pathogenic. -
Autosomal recessive distal spinal muscular atrophy 1 Pathogenic:1
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not provided Pathogenic:1
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 a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14681881, 27450922, 31980526) -
Charcot-Marie-Tooth disease axonal type 2S Pathogenic:1
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Charcot-Marie-Tooth disease Uncertain:1
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Neuronopathy, distal hereditary motor, autosomal dominant Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at