2-29717673-G-C
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_004304.5(ALK):c.692C>G(p.Thr231Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T231A) has been classified as Uncertain significance.
Frequency
Consequence
NM_004304.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.692C>G | p.Thr231Arg | missense_variant | 2/29 | ENST00000389048.8 | |
ALK | XR_001738688.3 | n.1619C>G | non_coding_transcript_exon_variant | 2/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.692C>G | p.Thr231Arg | missense_variant | 2/29 | 1 | NM_004304.5 | P1 | |
ALK | ENST00000618119.4 | c.-440C>G | 5_prime_UTR_variant | 1/28 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251402Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135864
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461794Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10AN XY: 727200
GnomAD4 genome ? AF: 0.000131 AC: 20AN: 152330Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74476
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 19, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 12, 2022 | The p.T231R variant (also known as c.692C>G), located in coding exon 2 of the ALK gene, results from a C to G substitution at nucleotide position 692. The threonine at codon 231 is replaced by arginine, an amino acid with similar properties. This amino acid position is conserved. 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. - |
Neuroblastoma, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 231 of the ALK protein (p.Thr231Arg). This variant is present in population databases (rs142120301, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ALK-related conditions. ClinVar contains an entry for this variant (Variation ID: 538218). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 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; This variant is associated with the following publications: (PMID: 25054154) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at