2-29197575-C-T
Variant summary
Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2
The NM_004304.5(ALK):c.4040G>A(p.Arg1347Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,730 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1347W) has been classified as Uncertain significance.
Frequency
Consequence
NM_004304.5 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Likely_benign. The variant received -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000318 AC: 8AN: 251398 AF XY: 0.0000368 show subpopulations
GnomAD4 exome AF: 0.0000472 AC: 69AN: 1461432Hom.: 0 Cov.: 32 AF XY: 0.0000564 AC XY: 41AN XY: 727030 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74472 show subpopulations
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1347 of the ALK protein (p.Arg1347Gln). This variant is present in population databases (rs573049471, gnomAD 0.006%). 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: 470861). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.R1347Q variant (also known as c.4040G>A), located in coding exon 27 of the ALK gene, results from a G to A substitution at nucleotide position 4040. The arginine at codon 1347 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at