chr14-74494829-AT-A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_194279.4(ISCA2):c.297delT(p.Phe99LeufsTer18) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,613,716 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_194279.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ISCA2 | NM_194279.4 | c.297delT | p.Phe99LeufsTer18 | frameshift_variant | Exon 4 of 4 | ENST00000556816.6 | NP_919255.2 | |
ISCA2 | NM_001272007.2 | c.181delT | p.Ter61GlufsTer56 | frameshift_variant, stop_lost | Exon 3 of 3 | NP_001258936.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ISCA2 | ENST00000556816.6 | c.297delT | p.Phe99LeufsTer18 | frameshift_variant | Exon 4 of 4 | 1 | NM_194279.4 | ENSP00000452007.1 | ||
ISCA2 | ENST00000554924.1 | c.181delT | p.Ter61GlufsTer56 | frameshift_variant, stop_lost | Exon 3 of 3 | 2 | ENSP00000450523.1 | |||
ISCA2 | ENST00000298818.12 | c.305-7delT | splice_region_variant, intron_variant | Intron 3 of 3 | 5 | ENSP00000298818.8 | ||||
ISCA2 | ENST00000555139.1 | n.735delT | non_coding_transcript_exon_variant | Exon 3 of 3 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152106Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250972Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135616
GnomAD4 exome AF: 0.0000691 AC: 101AN: 1461610Hom.: 0 Cov.: 31 AF XY: 0.0000619 AC XY: 45AN XY: 727118
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74294
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
ClinVar contains an entry for this variant (Variation ID: 545531). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This premature translational stop signal has been observed in individual(s) with clinical features consistent with multiple mitochondrial dysfunctions syndrome (PMID: 29359243). This variant is present in population databases (rs778755775, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Phe99Leufs*18) in the ISCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 56 amino acid(s) of the ISCA2 protein. -
The c.297delT variant has been published in a two month old presenting with severe hypotonia and nystagmus who had decreased activities of complex II and IV in muscle tissue and who harbored a second variant in the ISCA2 gene on the opposite allele (in trans) (Toldo et al., 2018). The c.297delT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The c.297delT variant causes a frameshift starting with codon Phenylalanine 99, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Phe99LeufsX18 (F99LfsX18). This variant is predicted to cause loss of normal protein function through protein truncation. In summary, we interpret c.297delT as a likely pathogenic variant. -
Multiple mitochondrial dysfunctions syndrome 4 Pathogenic:1Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at