rs28939681
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM5PP3_StrongPP5_Moderate
The NM_001540.5(HSPB1):c.406C>T(p.Arg136Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000552 in 1,449,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R136L) has been classified as Pathogenic.
Frequency
Consequence
NM_001540.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HSPB1 | NM_001540.5 | c.406C>T | p.Arg136Trp | missense_variant | 2/3 | ENST00000248553.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HSPB1 | ENST00000248553.7 | c.406C>T | p.Arg136Trp | missense_variant | 2/3 | 1 | NM_001540.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000704 AC: 1AN: 142092Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249202Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135528
GnomAD4 exome AF: 0.00000535 AC: 7AN: 1307308Hom.: 0 Cov.: 34 AF XY: 0.00000308 AC XY: 2AN XY: 648916
GnomAD4 genome ? AF: 0.00000704 AC: 1AN: 142092Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 68962
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease axonal type 2F Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 06, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg136 amino acid residue in HSPB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21611841, 22176143, 25547330). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects HSPB1 function (PMID: 18344398, 20178975, 22031878, 22521462, 28797631). 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 HSPB1 protein function. ClinVar contains an entry for this variant (Variation ID: 7482). This missense change has been observed in individual(s) with autosomal dominant Charcot-Marie-Tooth disease type 2 (PMID: 15122254). This variant is present in population databases (rs28939681, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 136 of the HSPB1 protein (p.Arg136Trp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at