rs61754865
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_004304.5(ALK):āc.2577G>Cā(p.Glu859Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,614,268 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. E859K) has been classified as Uncertain significance.
Frequency
Consequence
NM_004304.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.2577G>C | p.Glu859Asp | missense_variant | 15/29 | ENST00000389048.8 | |
ALK | XR_001738688.3 | n.3504G>C | non_coding_transcript_exon_variant | 15/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.2577G>C | p.Glu859Asp | missense_variant | 15/29 | 1 | NM_004304.5 | P1 | |
ALK | ENST00000618119.4 | c.1446G>C | p.Glu482Asp | missense_variant | 14/28 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000998 AC: 152AN: 152258Hom.: 2 Cov.: 34
GnomAD3 exomes AF: 0.000262 AC: 66AN: 251486Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135916
GnomAD4 exome AF: 0.000127 AC: 185AN: 1461892Hom.: 2 Cov.: 30 AF XY: 0.0000976 AC XY: 71AN XY: 727248
GnomAD4 genome AF: 0.00102 AC: 155AN: 152376Hom.: 2 Cov.: 34 AF XY: 0.00105 AC XY: 78AN XY: 74516
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 18, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2022 | ALK: BS1, BS2 - |
not specified Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2016 | This variant is denoted ALK c.2577G>C at the cDNA level, p.Glu859Asp (E859D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAC). This variant was identified in 1/43 healthy African individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. ALK Glu859Asp was observed with an allele frequency of 0.2% (10/4406) in African Americans in the NHLBI Exome Sequencing Project. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. ALK Glu859Asp occurs at a position that is conserved across species and is located in a Glycine rich region (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ALK Glu859Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Neuroblastoma, susceptibility to, 3 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | May 13, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at