chr9-105604483-C-CT
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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):c.642dup(p.Asp215Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
FKTN
NM_001079802.2 frameshift
NM_001079802.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0930
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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-105604483-C-CT is Pathogenic according to our data. Variant chr9-105604483-C-CT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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FKTN | NM_001079802.2 | c.642dup | p.Asp215Ter | frameshift_variant | 6/11 | ENST00000357998.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FKTN | ENST00000357998.10 | c.642dup | p.Asp215Ter | frameshift_variant | 6/11 | 5 | NM_001079802.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000136 AC: 34AN: 250372Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135366
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GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461464Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727082
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152266Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74456
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 16, 2023 | Observed in a patient with early-life epilepsy and structural brain malformation; zygosity was not explicitly stated (Berg et al., 2017); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22958903, 23757202, 28759667) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 06, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 30, 2015 | - - |
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Mar 22, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 21, 2020 | Variant summary: FKTN c.642dupT (p.Asp215X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00014 in 250372 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FKTN causing Walker-Warburg Syndrome (0.00014 vs 0.00046). c.642dupT has been reported in the literature in individuals affected with Walker-Warburg Syndrome (Manzini_2012, Berg_2017). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Walker-Warburg congenital muscular dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Asp215*) in the FKTN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FKTN are known to be pathogenic (PMID: 17044012, 17878207, 18752264). This variant is present in population databases (rs766898395, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with Walker-Warburg syndrome (PMID: 17878207, 22958903). ClinVar contains an entry for this variant (Variation ID: 93523). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 27, 2020 | - - |
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;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 21, 2021 | - - |
Dilated cardiomyopathy 1X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 09, 2022 | The c.642dupT pathogenic mutation, located in coding exon 4 of the FKTN gene, results from a duplication of T at nucleotide position 642, causing a translational frameshift with a predicted alternate stop codon (p.D215*). This variant has been detected in the homozygous state in an individual with Walker-Warburg syndrome and was also detected in an individual with early-onset epilepsy and brain malformation for whom zygosity detail was not provided (Manzini MC et al. Am J Hum Genet, 2012 Sep;91:541-7; Berg AT et al. JAMA Pediatr, 2017 Sep;171:863-871). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at