2-29346696-C-T

Variant names:

• chr2-29346696-C-T
• rs13000043
• NM_004304.5:c.1283-18215G>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.1283-18215G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 152,198 control chromosomes in the GnomAD database, including 2,848 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 0.18 (2848 hom., cov: 33)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.744
• Publications: 3 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000286963 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.1283-18215G>A		intron_variant	Intron 5 of 28	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.2210-18215G>A		intron_variant	Intron 5 of 17
LOC101929386	XR_007086263.1	n.448-4764C>T		intron_variant	Intron 3 of 4
LOC101929386	XR_939920.3	n.851-3468C>T		intron_variant	Intron 7 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.1283-18215G>A		intron_variant	Intron 5 of 28	1	NM_004304.5	ENSP00000373700.3

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26734 AN: 152080 Hom.: 2846 Cov.: 33

Gnomad AFR AF: 0.0716

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0194

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.192

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

GnomAD4 genome AF: 0.176 AC: 26737 AN: 152198 Hom.: 2848 Cov.: 33 AF XY: 0.174 AC XY: 12970 AN XY: 74430

African (AFR) AF: 0.0715 AC: 2967 AN: 41516

American (AMR) AF: 0.147 AC: 2244 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1010 AN: 3466

East Asian (EAS) AF: 0.0195 AC: 101 AN: 5192

South Asian (SAS) AF: 0.246 AC: 1187 AN: 4816

European-Finnish (FIN) AF: 0.218 AC: 2307 AN: 10596

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16213 AN: 67990

Other (OTH) AF: 0.189 AC: 399 AN: 2112

Alfa AF: 0.215 Hom.: 12223

Bravo AF: 0.160

Asia WGS AF: 0.110 AC: 385 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.67
PhyloP100		0.74
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: rs13000043; hg19: chr2-29569562;