rs2293563
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_004304.5(ALK):c.3036G>A(p.Thr1012=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,614,020 control chromosomes in the GnomAD database, including 23,683 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.18 ( 2540 hom., cov: 32)
Exomes 𝑓: 0.17 ( 21143 hom. )
Consequence
ALK
NM_004304.5 synonymous
NM_004304.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.19
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 Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
?
Variant 2-29226953-C-T is Benign according to our data. Variant chr2-29226953-C-T is described in ClinVar as [Benign]. Clinvar id is 259270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-29226953-C-T is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-3.19 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.3036G>A | p.Thr1012= | synonymous_variant | 18/29 | ENST00000389048.8 | |
ALK | XR_001738688.3 | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.3036G>A | p.Thr1012= | synonymous_variant | 18/29 | 1 | NM_004304.5 | P1 | |
ALK | ENST00000618119.4 | c.1905G>A | p.Thr635= | synonymous_variant | 17/28 | 5 | |||
ALK | ENST00000431873.6 | c.204G>A | p.Thr68= | synonymous_variant, NMD_transcript_variant | 2/14 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.177 AC: 26896AN: 152050Hom.: 2541 Cov.: 32
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GnomAD3 exomes AF: 0.156 AC: 39273AN: 251414Hom.: 3252 AF XY: 0.158 AC XY: 21531AN XY: 135876
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GnomAD4 exome AF: 0.167 AC: 244783AN: 1461852Hom.: 21143 Cov.: 35 AF XY: 0.168 AC XY: 122195AN XY: 727224
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GnomAD4 genome ? AF: 0.177 AC: 26894AN: 152168Hom.: 2540 Cov.: 32 AF XY: 0.173 AC XY: 12839AN XY: 74394
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ClinVar
Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Benign:4
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 06, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 27, 2016 | Variant summary: The c.3036G>A in ALK gene is a synonymous change that involves a non-conserved nucleotide. 3/5 splice-site tools in Alamut predict that this variant disrupts a cryptic splice donor site meanwhile creating a cryptic splice acceptor site as predicted by 2/5 tools; however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 16%. The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.0004%, suggesting that it is a benign polymorphism. The variant of interest has not been reported by reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 12, 2016 | This alteration is classified as 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
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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