9-105620049-GAAA-GAA
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001079802.2(FKTN):c.1167delA(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 (★★).
Frequency
Consequence
NM_001079802.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250506Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135522
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459614Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2AN XY: 726236
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1X Pathogenic:1
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not provided Pathogenic:1
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Cardiovascular phenotype Pathogenic:1
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
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at