rs17007646
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_004304.5(ALK):c.4165-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,613,500 control chromosomes in the GnomAD database, including 19,122 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).
Frequency
Consequence
NM_004304.5 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.4165-6C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000389048.8 | |||
ALK | NM_001353765.2 | c.961-6C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.4165-6C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_004304.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.196 AC: 29870AN: 152042Hom.: 3890 Cov.: 32
GnomAD3 exomes AF: 0.125 AC: 31187AN: 249008Hom.: 2850 AF XY: 0.120 AC XY: 16241AN XY: 135182
GnomAD4 exome AF: 0.133 AC: 193813AN: 1461340Hom.: 15231 Cov.: 35 AF XY: 0.130 AC XY: 94225AN XY: 726994
GnomAD4 genome ? AF: 0.196 AC: 29899AN: 152160Hom.: 3891 Cov.: 32 AF XY: 0.193 AC XY: 14364AN XY: 74402
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Benign:3
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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 | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 05, 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 | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 10, 2015 | - - |
Squamous cell lung carcinoma Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing;in vivo | Faculté Pluridciplinaire Nador, Université Mohamed Premier | May 05, 2020 | - - |
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 variant of interest is located at a non-conserved intronic position, not widely known to affect splicing, with 4/5 in silico programs via Alamut predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 15272/116488 (1/7 including 1465 homozygotes), which exceeds the predicted maximum expected allele frequency for a pathogenic ALK of 1/2500000. The variant of interest, to our knowledge, has not been published in affected individuals. A reputable clinical laboratory cites the variant with a classification of "benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at