rs74360487
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4
The NM_004304.5(ALK):c.2497G>T(p.Gly833Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,132 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 Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004304.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.2497G>T | p.Gly833Ter | stop_gained | 15/29 | ENST00000389048.8 | |
ALK | XR_001738688.3 | n.3424G>T | non_coding_transcript_exon_variant | 15/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.2497G>T | p.Gly833Ter | stop_gained | 15/29 | 1 | NM_004304.5 | P1 | |
ALK | ENST00000618119.4 | c.1366G>T | p.Gly456Ter | stop_gained | 14/28 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152246Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461886Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727248
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152246Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74366
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2023 | This sequence change creates a premature translational stop signal (p.Gly833*) in the ALK gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ALK cause disease. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ALK-related conditions. ClinVar contains an entry for this variant (Variation ID: 571876). 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. - |
ALK-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 15, 2023 | The ALK c.2497G>T variant is predicted to result in premature protein termination (p.Gly833*). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Loss of function variants in ALK are not an established mechanism of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at