9-105606576-G-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_001079802.2(FKTN):c.648-1243G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
FKTN
NM_001079802.2 intron
NM_001079802.2 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.100
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 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-105606576-G-T is Pathogenic according to our data. Variant chr9-105606576-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-105606576-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FKTN | NM_001079802.2 | c.648-1243G>T | intron_variant | ENST00000357998.10 | NP_001073270.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FKTN | ENST00000357998.10 | c.648-1243G>T | intron_variant | 5 | NM_001079802.2 | ENSP00000350687.6 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
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
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Dilated cardiomyopathy 1X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 24, 2024 | - - |
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 24, 2023 | Variant summary: FKTN c.648-1243G>T involves the alteration of a non-conserved nucleotide resulting in an intronic change. Several computational tools predict a significant impact on normal splicing: Two predict the variant strengthens a cryptic 5' donor site. One predicts the variant creates a cryptic 5' donor site. In addition, this variant is predicted to create a pseudoexon between exon 5 and exon 6 resulting in a frameshift and a premature stop codon (Kobayashi_2017). Another study showed patients with parental origins of this variant and direct sequencing of RNA showed the 64bp pseudogene insertion (Lim_2010). The variant was absent in 192 control chromosomes (gnomAD and publication data). c.648-1243G>T has been reported in the literature as a compound heterozygous genotype with a pathogenic variant in multiple individuals affected with Fukuyama Congenital Muscular Dystrophy (Example: Suzuki_2022, Kobayashi_2017, Lim_2010 etc.) and was shown to segregate with disease (Kobayashi_2017). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite this variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Walker-Warburg congenital muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 14, 2023 | This sequence change falls in intron 6 of the FKTN gene. It does not directly change the encoded amino acid sequence of the FKTN protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with congenital muscular dystrophy (PMID: 20620061, 28680109). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.647+2084G>T. ClinVar contains an entry for this variant (Variation ID: 496331). Studies have shown that this variant results in insertion of a pseudoexon and introduces a premature termination codon (PMID: 20620061, 28680109). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -6
Find out detailed SpliceAI scores and Pangolin per-transcript scores at