2-29232390-T-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_004304.5(ALK):c.2546A>C(p.Tyr849Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,128 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. Y849C) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.2546A>C | p.Tyr849Ser | missense_variant | 15/29 | ENST00000389048.8 | |
ALK | XR_001738688.3 | n.3473A>C | non_coding_transcript_exon_variant | 15/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.2546A>C | p.Tyr849Ser | missense_variant | 15/29 | 1 | NM_004304.5 | P1 | |
ALK | ENST00000618119.4 | c.1415A>C | p.Tyr472Ser | missense_variant | 14/28 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152234Hom.: 0 Cov.: 34
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461894Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727248
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152234Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3AN XY: 74366
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 849 of the ALK protein (p.Tyr849Ser). This variant is not present in population databases (gnomAD no frequency). 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: 956808). 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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 04, 2022 | The p.Y849S variant (also known as c.2546A>C), located in coding exon 15 of the ALK gene, results from an A to C substitution at nucleotide position 2546. The tyrosine at codon 849 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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