2-29297035-C-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_004304.5(ALK):c.1670G>A(p.Arg557His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R557C) has been classified as Likely benign.
Frequency
Consequence
NM_004304.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.1670G>A | p.Arg557His | missense_variant | Exon 9 of 29 | 1 | NM_004304.5 | ENSP00000373700.3 | ||
ALK | ENST00000618119.4 | c.539G>A | p.Arg180His | missense_variant | Exon 8 of 28 | 5 | ENSP00000482733.1 | |||
ALK | ENST00000498037.1 | n.225G>A | non_coding_transcript_exon_variant | Exon 3 of 5 | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152176Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251008Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135636
GnomAD4 exome AF: 0.0000349 AC: 51AN: 1461860Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29AN XY: 727232
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152176Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74336
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:3
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 557 of the ALK protein (p.Arg557His). This variant is present in population databases (rs200468507, gnomAD 0.007%). 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: 470766). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
not provided Uncertain:1
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25054154, 25668207) -
Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at