2-29251115-C-T
Variant summary
Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_004304.5(ALK):c.2194G>A(p.Asp732Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. D732Y) has been classified as Uncertain significance.
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: Benign. The variant received -7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.2194G>A | p.Asp732Asn | missense_variant | Exon 12 of 29 | 1 | NM_004304.5 | ENSP00000373700.3 | ||
ALK | ENST00000618119.4 | c.1063G>A | p.Asp355Asn | missense_variant | Exon 11 of 28 | 5 | ENSP00000482733.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152174Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000240 AC: 6AN: 249698 AF XY: 0.0000296 show subpopulations
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461732Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 727144 show subpopulations
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74320 show subpopulations
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:2
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This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 732 of the ALK protein (p.Asp732Asn). This variant is present in population databases (rs768366852, gnomAD 0.007%). 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: 576618). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Familial isolated pituitary adenoma Uncertain:1
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Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at