chr2-29193225-C-T
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2
The NM_004304.5(ALK):c.4862G>A(p.Ter1621=) variant causes a stop retained change. The variant allele was found at a frequency of 0.0000041 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
ALK
NM_004304.5 stop_retained
NM_004304.5 stop_retained
Scores
2
Clinical Significance
Conservation
PhyloP100: 3.99
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]
CLIP4 (HGNC:26108): (CAP-Gly domain containing linker protein family member 4) Predicted to enable microtubule plus-end binding activity. Predicted to be involved in cytoplasmic microtubule organization. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.28).
BP6
Variant 2-29193225-C-T is Benign according to our data. Variant chr2-29193225-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1668158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAdExome4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.4862G>A | p.Ter1621= | stop_retained_variant | 29/29 | ENST00000389048.8 | NP_004295.2 | |
ALK | NM_001353765.2 | c.1658G>A | p.Ter553= | stop_retained_variant | 10/10 | NP_001340694.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.4862G>A | p.Ter1621= | stop_retained_variant | 29/29 | 1 | NM_004304.5 | ENSP00000373700 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251266Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135802
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461650Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727120
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 04, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 12, 2023 | 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. - |
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