11-68906074-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002180.3(IGHMBP2):c.92G>A(p.Trp31Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
IGHMBP2
NM_002180.3 stop_gained
NM_002180.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 8.71
Genes affected
IGHMBP2 (HGNC:5542): (immunoglobulin mu DNA binding protein 2) This gene encodes a helicase superfamily member that binds a specific DNA sequence from the immunoglobulin mu chain switch region. Mutations in this gene lead to spinal muscle atrophy with respiratory distress type 1. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 181 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-68906074-G-A is Pathogenic according to our data. Variant chr11-68906074-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 242499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IGHMBP2 | NM_002180.3 | c.92G>A | p.Trp31Ter | stop_gained | 2/15 | ENST00000255078.8 | |
IGHMBP2 | XM_047426881.1 | c.92G>A | p.Trp31Ter | stop_gained | 2/15 | ||
IGHMBP2 | XM_017017671.3 | c.92G>A | p.Trp31Ter | stop_gained | 2/12 | ||
IGHMBP2 | XM_005273976.3 | c.92G>A | p.Trp31Ter | stop_gained | 2/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IGHMBP2 | ENST00000255078.8 | c.92G>A | p.Trp31Ter | stop_gained | 2/15 | 1 | NM_002180.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 01, 2023 | ClinVar contains an entry for this variant (Variation ID: 242499). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with distal spinomuscular atrophy (PMID: 25326637). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp31*) 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). - |
Ptosis;C0009024:Clonus;C0151889:Hyperreflexia;C0231835:Tachypnea;C0476273:Respiratory distress;C1839630:Severe muscular hypotonia;C2315100:Failure to thrive Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | Feb 16, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at