chr2-29920191-G-A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_004304.5(ALK):c.469C>T(p.Pro157Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000285 in 1,612,784 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P157L) 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 -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.469C>T | p.Pro157Ser | missense_variant | 1/29 | ENST00000389048.8 | |
ALK | XR_001738688.3 | n.1396C>T | non_coding_transcript_exon_variant | 1/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.469C>T | p.Pro157Ser | missense_variant | 1/29 | 1 | NM_004304.5 | P1 | |
ENST00000669284.1 | n.157+35058C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.000519 AC: 79AN: 152224Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000213 AC: 52AN: 244624Hom.: 0 AF XY: 0.000194 AC XY: 26AN XY: 133736
GnomAD4 exome AF: 0.000260 AC: 380AN: 1460560Hom.: 0 Cov.: 31 AF XY: 0.000311 AC XY: 226AN XY: 726596
GnomAD4 genome AF: 0.000519 AC: 79AN: 152224Hom.: 1 Cov.: 33 AF XY: 0.000471 AC XY: 35AN XY: 74358
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 05, 2023 | The ALK c.469C>T; p.Pro157Ser variant (rs74774946), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 239842). This variant is found in the non-Finnish European population with an allele frequency of 0.063% (79/125,556 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.031). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 19, 2023 | 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:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 30, 2018 | The p.P157S variant (also known as c.469C>T), located in coding exon 1 of the ALK gene, results from a C to T substitution at nucleotide position 469. The proline at codon 157 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. 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. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 05, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at