chr9-105635056-T-C
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.
The NM_001079802.2(FKTN):c.1178T>C(p.Leu393Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L393M) has been classified as Uncertain significance.
Frequency
Consequence
NM_001079802.2 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive limb-girdle muscular dystrophy type 2MInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
- muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
- myopathy caused by variation in FKTNInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- congenital muscular dystrophy without intellectual disabilityInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- muscle-eye-brain diseaseInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- muscular dystrophy-dystroglycanopathy, type AInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- dilated cardiomyopathy 1XInheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.0000119 AC: 3AN: 251338 AF XY: 0.0000221 show subpopulations
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461738Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727184 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Walker-Warburg congenital muscular dystrophy Uncertain:2
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This sequence change replaces leucine with proline at codon 393 of the FKTN protein (p.Leu393Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs374962879, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with FKTN-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Cardiovascular phenotype Uncertain:1
The p.L393P variant (also known as c.1178T>C), located in coding exon 9 of the FKTN gene, results from a T to C substitution at nucleotide position 1178. The leucine at codon 393 is replaced by proline, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at