rs752358445
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_001079802.2(FKTN):c.1270G>A(p.Gly424Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001079802.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FKTN | NM_001079802.2 | c.1270G>A | p.Gly424Ser | missense_variant | 11/11 | ENST00000357998.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FKTN | ENST00000357998.10 | c.1270G>A | p.Gly424Ser | missense_variant | 11/11 | 5 | NM_001079802.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251418Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135874
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461748Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727170
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74310
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1X Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 23, 2023 | - - |
Primary familial dilated cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 09, 2023 | Variant summary: FKTN c.1270G>A (p.Gly424Ser) results in a non-conservative amino acid change located in the region involved in the phosphorylation of the C-terminal end (Larranaga-Moreira_2021) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251418 control chromosomes (gnomAD). c.1270G>A has been reported in the literature in multiple individuals affected with Dilated Cardiomyopathy and this variant co-segregated with the disease in two unrelated families (example: Larranaga-Moreira_2021, Villarreal-Molina_2020, Winckler_2022). These data indicate that the variant is very likely to be associated with disease. Additionally, a muscle biopsy from the homozygous individual in Larranaga-Moreira_2021 showed severe reduction in alpha-dystroglycan and slight reduction in laminin alpha2 compared with healthy control. The following publications have been ascertained in the context of this evaluation (PMID: 32969603, 34120883, 33048919, 35175440). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 14, 2016 | - - |
Walker-Warburg congenital muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 05, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 424 of the FKTN protein (p.Gly424Ser). This variant is present in population databases (rs752358445, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of muscular dystrophy-dystroglycanopathy (PMID: 32969603, 34120883; Invitae). ClinVar contains an entry for this variant (Variation ID: 290602). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at