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
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
FKTN
NM_001079802.2 disruptive_inframe_deletion
NM_001079802.2 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.54
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 Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_001079802.2.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant 9-105635090-TGTAGACATGAAG-T is Pathogenic according to our data. Variant chr9-105635090-TGTAGACATGAAG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 431957.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=3}. Variant chr9-105635090-TGTAGACATGAAG-T is described in Lovd as [Pathogenic]. Variant chr9-105635090-TGTAGACATGAAG-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251360Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135842
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461856Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727234
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GnomAD4 genome 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 Pathogenic:1Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 06, 2017 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 01, 2021 | PM2, PM4, PP4, PP5 - |
Walker-Warburg congenital muscular dystrophy Uncertain:2
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 18, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 13, 2021 | 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. - |
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
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 07, 2024 | - - |
Dilated cardiomyopathy 1X Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 11, 2023 | - - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 23, 2017 | 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
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at