rs149185954
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_002180.3(IGHMBP2):c.2295C>G(p.His765Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. H765H) has been classified as Likely benign.
Frequency
Consequence
NM_002180.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IGHMBP2 | NM_002180.3 | c.2295C>G | p.His765Gln | missense_variant | 13/15 | ENST00000255078.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IGHMBP2 | ENST00000255078.8 | c.2295C>G | p.His765Gln | missense_variant | 13/15 | 1 | NM_002180.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152212Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251162Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135800
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461706Hom.: 0 Cov.: 43 AF XY: 0.0000110 AC XY: 8AN XY: 727168
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74364
ClinVar
Submissions by phenotype
Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 03, 2022 | This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 765 of the IGHMBP2 protein (p.His765Gln). This variant is present in population databases (rs149185954, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with IGHMBP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 466589). 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 not expected to disrupt IGHMBP2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 25, 2021 | The p.H765Q variant (also known as c.2295C>G), located in coding exon 13 of the IGHMBP2 gene, results from a C to G substitution at nucleotide position 2295. The histidine at codon 765 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at