rs1554766855
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM4PP3PP5
The NM_001079802.2(FKTN):c.1215_1226delAGACATGAAGGT(p.Asp406_Val409del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001079802.2 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251360Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135842
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461856Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727234
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356
ClinVar
Submissions by phenotype
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 Pathogenic:1Uncertain:1
PM2, PM4, PP4, PP5 -
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Walker-Warburg congenital muscular dystrophy Uncertain:2
This variant, c.1215_1226del, results in the deletion of 4 amino acid(s) of the FKTN protein (p.Asp406_Val409del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Walker-Warburg syndrome (PMID: 20961758). ClinVar contains an entry for this variant (Variation ID: 431957). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4;C1969024:Dilated cardiomyopathy 1X;C1969040:Autosomal recessive limb-girdle muscular dystrophy type 2M;C2751052:Muscular dystrophy-dystroglycanopathy (congenital without intellectual disability), type B4 Pathogenic:1
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Dilated cardiomyopathy 1X Pathogenic:1
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not provided Uncertain:1
A variant of uncertain significance has been identified in the FKTN gene. The c.1215_1226del12 variant has been reported in a female infant of Greek and Croatian ancestry, who was diagnosed with Walker-Warburg syndrome and also harbored the R47X variant in the FKTN gene and the R95C variant in the FKRP gene (Yis et al., 2011). Parental testing revealed that the c.1215_1226del12 variant in the FKTN gene was maternally inherited, and the R47X variant in the FKTN gene reportedly occurred de novo in this infant (Yis et al., 2011); although parental identity testing and/or additional studies to confirm whether the two FKTN variants were on the same or opposite alleles were not reported. The c.1215_1226del12 variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.1215_1226del12 variant results in the in-frame deletion of four amino acids, from aspartic acid (D) 406 to valine (V) 409, denoted p.Asp406_Val409del. However, no other in-frame deletions have been reported in HGMD in association with FKTN-related disorders (Stenson et al., 2014). Furthermore, in the absence of functional expression studies, the physiological consequence of this variant cannot be precisely determined. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at