rs200641396
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_004304.5(ALK):c.3133G>C(p.Val1045Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,212 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V1045M) has been classified as Likely benign.
Frequency
Consequence
NM_004304.5 missense
Scores
Clinical Significance
Conservation
Publications
- neuroblastoma, susceptibility to, 3Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.3133G>C | p.Val1045Leu | missense_variant | Exon 19 of 29 | 1 | NM_004304.5 | ENSP00000373700.3 | ||
ALK | ENST00000618119.4 | c.2002G>C | p.Val668Leu | missense_variant | Exon 18 of 28 | 5 | ENSP00000482733.1 | |||
ALK | ENST00000431873.6 | n.298G>C | non_coding_transcript_exon_variant | Exon 3 of 14 | 5 | ENSP00000414027.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461212Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726768 show subpopulations
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:1
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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ALK-related disease. ClinVar contains an entry for this variant (Variation ID: 470817). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 1045 of the ALK protein (p.Val1045Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at