2-29239766-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_004304.5(ALK):c.2269G>A(p.Val757Met) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V757A) has been classified as Uncertain significance.
Frequency
Consequence
NM_004304.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.2269G>A | p.Val757Met | missense_variant | Exon 13 of 29 | 1 | NM_004304.5 | ENSP00000373700.3 | ||
ALK | ENST00000618119.4 | c.1138G>A | p.Val380Met | missense_variant | Exon 12 of 28 | 5 | ENSP00000482733.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251180Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135770
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461754Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727184
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74328
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:3
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This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 757 of the ALK protein (p.Val757Met). This variant is present in population databases (rs371005946, 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: 470785). 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. -
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Ovarian cancer Pathogenic:1
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not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as a germline pathogenic or benign variant to our knowledge; This variant is associated with the following publications: (PMID: 24710307) -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.V757M variant (also known as c.2269G>A), located in coding exon 13 of the ALK gene, results from a G to A substitution at nucleotide position 2269. The valine at codon 757 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at