chr2-29193232-C-CAGGCTGGTTCATGCTATTCTTGCTTTT
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
The NM_004304.5(ALK):c.4854_4855insAAAAGCAAGAATAGCATGAACCAGCCT(p.Lys1610_Pro1618dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
ALK
NM_004304.5 inframe_insertion
NM_004304.5 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -2.18
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]
CLIP4 (HGNC:26108): (CAP-Gly domain containing linker protein family member 4) Predicted to enable microtubule plus-end binding activity. Predicted to be involved in cytoplasmic microtubule organization. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_004304.5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.4854_4855insAAAAGCAAGAATAGCATGAACCAGCCT | p.Lys1610_Pro1618dup | inframe_insertion | 29/29 | ENST00000389048.8 | |
ALK | NM_001353765.2 | c.1650_1651insAAAAGCAAGAATAGCATGAACCAGCCT | p.Lys542_Pro550dup | inframe_insertion | 10/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.4854_4855insAAAAGCAAGAATAGCATGAACCAGCCT | p.Lys1610_Pro1618dup | inframe_insertion | 29/29 | 1 | NM_004304.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461760Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727168
GnomAD4 exome
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AN:
1461760
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31
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0
AN XY:
727168
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 06, 2020 | Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with ALK-related conditions. This variant is not present in population databases (ExAC no frequency). This variant, c.4828_4854dup, results in the insertion of 9 amino acid(s) to the ALK protein (p.Lys1610_Pro1618dup), but otherwise preserves the integrity of the reading frame. 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. - |
Computational scores
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Name
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Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at