2-29318329-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_004304.5(ALK):c.1622C>A(p.Ala541Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign 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. A541P) has been classified as Uncertain significance.
Frequency
Consequence
NM_004304.5 missense
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.1622C>A | p.Ala541Glu | missense_variant | 8/29 | ENST00000389048.8 | |
ALK | XR_001738688.3 | n.2549C>A | non_coding_transcript_exon_variant | 8/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.1622C>A | p.Ala541Glu | missense_variant | 8/29 | 1 | NM_004304.5 | P1 | |
ALK | ENST00000618119.4 | c.491C>A | p.Ala164Glu | missense_variant | 7/28 | 5 | |||
ALK | ENST00000498037.1 | n.177C>A | non_coding_transcript_exon_variant | 2/5 | 4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 18, 2017 | This sequence change replaces alanine with glutamic acid at codon 541 of the ALK protein (p.Ala541Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ALK-related disease. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at