rs886042506
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024301.5(FKRP):c.162_165dupGGAG(p.Phe56GlyfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000237 in 1,604,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_024301.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FKRP | NM_024301.5 | c.162_165dupGGAG | p.Phe56GlyfsTer6 | frameshift_variant | Exon 4 of 4 | ENST00000318584.10 | NP_077277.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152178Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000862 AC: 2AN: 232120Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 126546
GnomAD4 exome AF: 0.0000234 AC: 34AN: 1452756Hom.: 0 Cov.: 33 AF XY: 0.0000263 AC XY: 19AN XY: 722400
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74334
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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PM2, PS4_moderate, PVS1 -
The FKRP c.162_165dup; p.Phe56GlyfsTer6 variant (rs886042506; also reported as 165InsGGAG; ClinVar Variation ID: 282866), has been previously identified in trans with other pathogenic variants in FKRP in at least two patients with symptoms of congenital muscular dystrophy and reduced glycosylated alpha-dystroglycan (Brockington 2001 and Peat 2008). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last (and only coding) exon of the FKRP gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein that would include a sequence of 6 amino acid residues not usually present. Additionally, several downstream truncating variants have been described in individuals with FKRP-related muscular dystrophy and are considered pathogenic (Selected references: Brockington 2001 and Matsumoto 2005). Based on the available information, the p.Phe56GlyfsTer6 variant is considered pathogenic. References: Brockington M et al. Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am J Hum Genet. 2001 Dec;69(6):1198-209. PMID: 11592034 Matsumoto H et al. Congenital muscular dystrophy with glycosylation defects of alpha-dystroglycan in Japan. Neuromuscul Disord. 2005 May;15(5):342-8. PMID: 15833426. Peat RA et al. Diagnosis and etiology of congenital muscular dystrophy. Neurology. 2008 Jul 29;71(5):312-21. PMID: 18160674. -
Autosomal recessive limb-girdle muscular dystrophy type 2I;C1847759:Muscular dystrophy-dystroglycanopathy type B5;C3150413:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 Pathogenic:2
FKRP NM_024301.4 ex 4 p.Phe56Glyfs*6 (c.162_165dup): This variant has been reported in the literature in at least one individual with autosomal congenital muscular dystrophy (Brockington 2001 PMID:11592034). This variant is present in 0.001% (2/104602) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/19-47258867-C-CGGGA) and is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:282866). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop codon 6 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene (Thornhill 2008 PMID:18477595). In summary, this variant is classified as pathogenic based on the data above. -
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Autosomal recessive limb-girdle muscular dystrophy type 2I Pathogenic:1
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Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1
Variant summary: FKRP c.162_165dupGGAG (p.Phe56GlyfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.6e-06 in 232120 control chromosomes. c.162_165dupGGAG has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. Additionally, variants downstream of this position have been classified as pathogenic by our lab. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 282866). Based on the evidence outlined above, the variant was classified as pathogenic. -
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 Pathogenic:1
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Walker-Warburg congenital muscular dystrophy Pathogenic:1
This sequence change creates a premature translational stop signal (p.Phe56Glyfs*6) in the FKRP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 440 amino acid(s) of the FKRP protein. This variant is present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with FKRP-related conditions (PMID: 11592034, 18160674). ClinVar contains an entry for this variant (Variation ID: 282866). This variant disrupts a region of the FKRP protein in which other variant(s) (p.Q460*) have been determined to be pathogenic (PMID: 16476814; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at