rs34658653
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_002180.3(IGHMBP2):c.1821C>T(p.His607=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000796 in 1,614,166 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0040 ( 2 hom., cov: 33)
Exomes 𝑓: 0.00047 ( 3 hom. )
Consequence
IGHMBP2
NM_002180.3 synonymous
NM_002180.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.63
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 Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.51).
BP6
?
Variant 11-68936301-C-T is Benign according to our data. Variant chr11-68936301-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=-1.63 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00397 (604/152308) while in subpopulation AFR AF= 0.0132 (550/41562). AF 95% confidence interval is 0.0123. There are 2 homozygotes in gnomad4. There are 276 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IGHMBP2 | NM_002180.3 | c.1821C>T | p.His607= | synonymous_variant | 13/15 | ENST00000255078.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IGHMBP2 | ENST00000255078.8 | c.1821C>T | p.His607= | synonymous_variant | 13/15 | 1 | NM_002180.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00396 AC: 603AN: 152190Hom.: 2 Cov.: 33
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GnomAD3 exomes AF: 0.000955 AC: 240AN: 251366Hom.: 1 AF XY: 0.000662 AC XY: 90AN XY: 135874
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GnomAD4 exome AF: 0.000466 AC: 681AN: 1461858Hom.: 3 Cov.: 32 AF XY: 0.000415 AC XY: 302AN XY: 727238
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GnomAD4 genome ? AF: 0.00397 AC: 604AN: 152308Hom.: 2 Cov.: 33 AF XY: 0.00371 AC XY: 276AN XY: 74474
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | IGHMBP2: BP4, BP7, BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2020 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Charcot-Marie-Tooth disease Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Autosomal recessive distal spinal muscular atrophy 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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