2-29264409-C-T

Variant names:

• chr2-29264409-C-T
• rs1358514
• NM_004304.5:c.2041+10690G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004304.5(ALK):​c.2041+10690G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.599 in 152,158 control chromosomes in the GnomAD database, including 29,284 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.60 (29284 hom., cov: 34)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.446
• Publications: 2 publications found

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]

ALK Gene-Disease associations (from GenCC):

• neuroblastoma, susceptibility to, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004304.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	NM_004304.5	MANE Select	c.2041+10690G>A		intron	N/A	NP_004295.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.2041+10690G>A		intron	N/A	ENSP00000373700.3	Q9UM73
	ALK	ENST00000618119.4	TSL:5	c.910+10690G>A		intron	N/A	ENSP00000482733.1	A0A087WZL3

Frequencies

GnomAD3 genomes AF: 0.599 AC: 91079 AN: 152040 Hom.: 29273 Cov.: 34

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.673

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.757

Gnomad SAS AF: 0.686

Gnomad FIN AF: 0.742

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.693

Gnomad OTH AF: 0.589

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

GnomAD4 genome AF: 0.599 AC: 91120 AN: 152158 Hom.: 29284 Cov.: 34 AF XY: 0.605 AC XY: 44979 AN XY: 74384

African (AFR) AF: 0.347 AC: 14400 AN: 41496

American (AMR) AF: 0.674 AC: 10308 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 2096 AN: 3470

East Asian (EAS) AF: 0.756 AC: 3914 AN: 5174

South Asian (SAS) AF: 0.686 AC: 3310 AN: 4822

European-Finnish (FIN) AF: 0.742 AC: 7858 AN: 10596

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.693 AC: 47130 AN: 67990

Other (OTH) AF: 0.592 AC: 1250 AN: 2110

Alfa AF: 0.660 Hom.: 12838

Bravo AF: 0.582

Asia WGS AF: 0.714 AC: 2482 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.80
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1358514; hg19: chr2-29487275;