rs119464997
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_001079802.2(FKTN):c.509C>A(p.Ala170Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,828 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A170T) has been classified as Uncertain significance.
Frequency
Consequence
NM_001079802.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FKTN | NM_001079802.2 | c.509C>A | p.Ala170Glu | missense_variant | 6/11 | ENST00000357998.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FKTN | ENST00000357998.10 | c.509C>A | p.Ala170Glu | missense_variant | 6/11 | 5 | NM_001079802.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461828Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727234
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1X Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 19, 2023 | - - |
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 09, 2012 | - - |
Walker-Warburg congenital muscular dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 170 of the FKTN protein (p.Ala170Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with FKTN-related conditions (PMID: 19179078). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3214). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FKTN protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects FKTN function (PMID: 22275357). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at