rs1010580453
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_004304.5(ALK):āc.1725G>Cā(p.Lys575Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000083 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Exomes š: 0.000091 ( 0 hom. )
Consequence
ALK
NM_004304.5 missense
NM_004304.5 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: 2.44
Genes affected
ALK (HGNC:427): (ALK receptor tyrosine kinase) This gene encodes a receptor tyrosine kinase, which belongs to the insulin receptor superfamily. This protein comprises an extracellular domain, an hydrophobic stretch corresponding to a single pass transmembrane region, and an intracellular kinase domain. It plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. This gene has been found to be rearranged, mutated, or amplified in a series of tumours including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer. The chromosomal rearrangements are the most common genetic alterations in this gene, which result in creation of multiple fusion genes in tumourigenesis, including ALK (chromosome 2)/EML4 (chromosome 2), ALK/RANBP2 (chromosome 2), ALK/ATIC (chromosome 2), ALK/TFG (chromosome 3), ALK/NPM1 (chromosome 5), ALK/SQSTM1 (chromosome 5), ALK/KIF5B (chromosome 10), ALK/CLTC (chromosome 17), ALK/TPM4 (chromosome 19), and ALK/MSN (chromosome X).[provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
High AC in GnomAdExome4 at 133 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.1725G>C | p.Lys575Asn | missense_variant | 9/29 | ENST00000389048.8 | NP_004295.2 | |
ALK | XR_001738688.3 | n.2652G>C | non_coding_transcript_exon_variant | 9/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.1725G>C | p.Lys575Asn | missense_variant | 9/29 | 1 | NM_004304.5 | ENSP00000373700 | P1 | |
ALK | ENST00000618119.4 | c.594G>C | p.Lys198Asn | missense_variant | 8/28 | 5 | ENSP00000482733 | |||
ALK | ENST00000498037.1 | n.280G>C | non_coding_transcript_exon_variant | 3/5 | 4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152238Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251174Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135736
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GnomAD4 exome AF: 0.0000910 AC: 133AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.0000880 AC XY: 64AN XY: 727244
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152238Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74378
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 22, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 575 of the ALK protein (p.Lys575Asn). This variant is present in population databases (no rsID available, gnomAD 0.004%). 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: 470771). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 12, 2023 | The p.K575N variant (also known as c.1725G>C), located in coding exon 9 of the ALK gene, results from a G to C substitution at nucleotide position 1725. The lysine at codon 575 is replaced by asparagine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.
REVEL
Benign
Sift
Benign
T;.
Sift4G
Benign
T;T
Polyphen
P;.
Vest4
MutPred
Loss of solvent accessibility (P = 0.0079);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at