2-29193219-CGAGCTCA-C

Variant names:

• chr2-29193219-CGAGCTCA-C
• NM_004304.5:c.4861_*4delTGAGCTC

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_004304.5(ALK):​c.4861_*4delTGAGCTC​(p.Ter1621fs) variant causes a frameshift, stop lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. *1621*) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALK NM_004304.5 frameshift, stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_004304.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.4861_*4delTGAGCTC	p.Ter1621fs	frameshift_variant, stop_lost	Exon 29 of 29	ENST00000389048.8	NP_004295.2
ALK	NM_004304.5	c.4860_*4delTGAGCTC		3_prime_UTR_variant	Exon 29 of 29	ENST00000389048.8	NP_004295.2
ALK	NM_001353765.2	c.1657_*4delTGAGCTC	p.Ter553fs	frameshift_variant, stop_lost	Exon 10 of 10		NP_001340694.1
ALK	NM_001353765.2	c.1656_*4delTGAGCTC		3_prime_UTR_variant	Exon 10 of 10		NP_001340694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.4861_*4delTGAGCTC	p.Ter1621fs	frameshift_variant, stop_lost	Exon 29 of 29	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000389048	c.4860_*4delTGAGCTC		3_prime_UTR_variant	Exon 29 of 29	1	NM_004304.5	ENSP00000373700.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Uncertain:1

Dec 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change disrupts the translational stop signal of the ALK mRNA. It is expected to extend the length of the ALK protein by 11 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ALK-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-29416085;