rs770111639
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_002180.3(IGHMBP2):c.1693G>A(p.Asp565Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,614,040 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 (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
IGHMBP2
NM_002180.3 missense
NM_002180.3 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 9.42
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 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 11-68935359-G-A is Pathogenic according to our data. Variant chr11-68935359-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 581680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68935359-G-A is described in Lovd as [Pathogenic]. Variant chr11-68935359-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
IGHMBP2 | NM_002180.3 | c.1693G>A | p.Asp565Asn | missense_variant | 12/15 | ENST00000255078.8 | NP_002171.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IGHMBP2 | ENST00000255078.8 | c.1693G>A | p.Asp565Asn | missense_variant | 12/15 | 1 | NM_002180.3 | ENSP00000255078.4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152260Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251404Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135900
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GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461780Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 727200
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152260Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74382
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6Uncertain:1
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:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 14, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 565 of the IGHMBP2 protein (p.Asp565Asn). This variant is present in population databases (rs770111639, gnomAD 0.01%). This missense change has been observed in individual(s) with distal hereditary motor neuropathy, type VI (PMID: 14681881, 15108294, 22157136). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 581680). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IGHMBP2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects IGHMBP2 function (PMID: 19158098, 22157136). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 07, 2024 | - - |
Charcot-Marie-Tooth disease axonal type 2S Pathogenic:2
Likely pathogenic, no assertion criteria provided | case-control | Biochemistry Laboratory of CDMU, Chengde Medical University | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 01, 2024 | Variant summary: IGHMBP2 c.1693G>A (p.Asp565Asn) results in a conservative amino acid change located in the DNA2/NAM7 helicase-like, C-terminal domain (IPR041679) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251404 control chromosomes. c.1693G>A has been reported in the literature in at-least two individuals affected with Charcot-Marie-Tooth Disease, Axonal, Type 2S and Spinal Muscular Atrophy with Respiratory Distress (examples, Maystadt_2004, Xiao_2022, Gao_2019). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in completely inactive in the helicase assay, but still retained its full nucleic acid binding capacity in FM3A cells (Guenther_2009). The following publications have been ascertained in the context of this evaluation (PMID: 34986626, 31178897, 19158098, 15108294). ClinVar contains an entry for this variant (Variation ID: 581680). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 12, 2021 | The c.1693G>A (p.D565N) alteration is located in exon 12 (coding exon 12) of the IGHMBP2 gene. This alteration results from a G to A substitution at nucleotide position 1693, causing the aspartic acid (D) at amino acid position 565 to be replaced by an asparagine (N). Based on data from the Genome Aggregation Database (gnomAD) database, the IGHMBP2 c.1693G>A alteration was observed in 0.002% (7/282810) of total alleles studied, with a frequency of 0.01% (1/10370) in the Ashkenazi Jewish subpopulation. This alteration has been reported in trans with a pathogenic alteration in an individual with spinal muscular atrophy 1 with respiratory distress (SMARD1) (Maystadt, 2004). It was also reported in trans with a different alteration in a child with developmental delay, motor deterioration, myotonia, reduced tendon reflexes, slurred speech, abnormal posturing, poor fine motor coordination, peripheral neuropathy, talipes equinovarus, and EMG abnormality (Gao, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration has also been shown to impair protein function (Eckart, 2012; Guenther, 2009). The in silico prediction for the p.D565N alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | IGHMBP2: PM3:Very Strong, PM2, PP3, PS3:Supporting - |
Distal spinal muscular atrophy Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of ubiquitination at K562 (P = 0.0755);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at