rs104894682
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong
The NM_024301.5(FKRP):c.1486T>A(p.Ter496ArgextTer21) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
FKRP
NM_024301.5 stop_lost
NM_024301.5 stop_lost
Scores
1
2
4
Clinical Significance
Conservation
PhyloP100: 2.85
Genes affected
FKRP (HGNC:17997): (fukutin related protein) This gene encodes a protein which is targeted to the medial Golgi apparatus and is necessary for posttranslational modification of dystroglycan. Mutations in this gene have been associated with congenital muscular dystrophy, cognitive disability, and cerebellar cysts. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Stoplost variant in NM_024301.5 Downstream stopcodon found after 590 codons.
PP5
?
Variant 19-46756936-T-A is Pathogenic according to our data. Variant chr19-46756936-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46756936-T-A is described in Lovd as [Pathogenic]. Variant chr19-46756936-T-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FKRP | NM_024301.5 | c.1486T>A | p.Ter496ArgextTer21 | stop_lost | 4/4 | ENST00000318584.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FKRP | ENST00000318584.10 | c.1486T>A | p.Ter496ArgextTer21 | stop_lost | 4/4 | 1 | NM_024301.5 | P1 | |
FKRP | ENST00000391909.7 | c.1486T>A | p.Ter496ArgextTer21 | stop_lost | 4/4 | 2 | P1 | ||
FKRP | ENST00000597339.5 | n.247-4897T>A | intron_variant, non_coding_transcript_variant | 5 | |||||
FKRP | ENST00000600646.5 | n.247+8271T>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152154Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000813 AC: 2AN: 245964Hom.: 0 AF XY: 0.00000745 AC XY: 1AN XY: 134250
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460586Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726564
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2I Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 09, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 22, 2003 | - - |
Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 01, 2022 | Variant summary: FKRP c.1486T>A (p.X496ArgextX21) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. The variant allele was found at a frequency of 8.1e-06 in 245964 control chromosomes (gnomAD). c.1486T>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy and vacuolar myopathy (examples: Driss_2003, Kefi_2008, Mair_2020, Walter_FKRP_2004). The variant also seggregated with disease. These data indicate that the variant is very likely to be associated with disease. Driss_2003 demonstrated that this variant reduced alpha dystroglycan and laminin levels in isolated muscle protein immmunoblots. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=4) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Muscular dystrophy-dystroglycanopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 13, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 25, 2017 | - - |
Walker-Warburg congenital muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change disrupts the translational stop signal of the FKRP mRNA. It is expected to extend the length of the FKRP protein by 21 additional amino acid residues. This variant is present in population databases (rs104894682, gnomAD 0.0009%). This protein extension has been observed in individuals with limb girdle muscular dystrophy (PMID: 10838249, 12707439, 15060126, 18671187). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4223). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
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