rs116202066
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_004304.5(ALK):c.1943C>T(p.Thr648Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000424 in 1,614,170 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T648A) has been classified as Uncertain significance.
Frequency
Consequence
NM_004304.5 missense
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.1943C>T | p.Thr648Ile | missense_variant | 11/29 | ENST00000389048.8 | |
ALK | XR_001738688.3 | n.2870C>T | non_coding_transcript_exon_variant | 11/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.1943C>T | p.Thr648Ile | missense_variant | 11/29 | 1 | NM_004304.5 | P1 | |
ALK | ENST00000618119.4 | c.812C>T | p.Thr271Ile | missense_variant | 10/28 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00215 AC: 328AN: 152204Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000565 AC: 142AN: 251472Hom.: 3 AF XY: 0.000383 AC XY: 52AN XY: 135908
GnomAD4 exome AF: 0.000243 AC: 355AN: 1461848Hom.: 3 Cov.: 32 AF XY: 0.000213 AC XY: 155AN XY: 727228
GnomAD4 genome ? AF: 0.00217 AC: 330AN: 152322Hom.: 1 Cov.: 33 AF XY: 0.00212 AC XY: 158AN XY: 74488
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Benign:3
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 30, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 29, 2018 | 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. - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 06, 2020 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 19, 2023 | See Variant Classification Assertion Criteria. - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at