rs398123555
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001079802.2(FKTN):βc.1167delβ(p.Lys389AsnfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,614 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ).
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000014 ( 0 hom. )
Consequence
FKTN
NM_001079802.2 frameshift
NM_001079802.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.53
Genes affected
FKTN (HGNC:3622): (fukutin) The protein encoded by this gene is a putative transmembrane protein that is localized to the cis-Golgi compartment, where it may be involved in the glycosylation of alpha-dystroglycan in skeletal muscle. The encoded protein is thought to be a glycosyltransferase and could play a role in brain development. Defects in this gene are a cause of Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), limb-girdle muscular dystrophy type 2M (LGMD2M), and dilated cardiomyopathy type 1X (CMD1X). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 20 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-105620049-GA-G is Pathogenic according to our data. Variant chr9-105620049-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 1322920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-105620049-GA-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FKTN | NM_001079802.2 | c.1167del | p.Lys389AsnfsTer17 | frameshift_variant | 10/11 | ENST00000357998.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FKTN | ENST00000357998.10 | c.1167del | p.Lys389AsnfsTer17 | frameshift_variant | 10/11 | 5 | NM_001079802.2 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250506Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135522
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459614Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2AN XY: 726236
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Dilated cardiomyopathy 1X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 02, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 10, 2020 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 01, 2022 | The c.1167delA pathogenic mutation, located in coding exon 8 of the FKTN gene, results from a deletion of one nucleotide at nucleotide position 1167, causing a translational frameshift with a predicted alternate stop codon (p.K389Nfs*17). This alteration occurs at the 3' terminus of theFKTN gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 72 amino acids (15%) of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). A different variant resulting in a similar protein impact (c.1167dupA, p.F390Ifs*14) has been reported in association with congenital muscular dystrophy and Walker-Warburg syndrome (Kondo-Iida E et al. Hum. Mol. Genet., 1999 Nov;8:2303-9; Chang W et al. Prenat. Diagn., 2009 Jun;29:560-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Walker-Warburg congenital muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change creates a premature translational stop signal (p.Lys389Asnfs*17) in the FKTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acid(s) of the FKTN protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with FKTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1322920). This variant disrupts a region of the FKTN protein in which other variant(s) (p.Tyr392*) have been determined to be pathogenic (PMID: 22522420; Invitae). 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
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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