NM_004304.5:c.668-18278G>A

Variant names:

• chr2-29735975-C-T
• rs2631958
• NM_004304.5:c.668-18278G>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.668-18278G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.856 in 151,978 control chromosomes in the GnomAD database, including 55,965 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 0.86 (55965 hom., cov: 30)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.713
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.668-18278G>A		intron_variant	Intron 1 of 28	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.1595-18278G>A		intron_variant	Intron 1 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.668-18278G>A		intron_variant	Intron 1 of 28	1	NM_004304.5	ENSP00000373700.3

Frequencies

GnomAD3 genomes AF: 0.856 AC: 129988 AN: 151864 Hom.: 55905 Cov.: 30

Gnomad AFR AF: 0.924

Gnomad AMI AF: 0.951

Gnomad AMR AF: 0.796

Gnomad ASJ AF: 0.884

Gnomad EAS AF: 0.824

Gnomad SAS AF: 0.843

Gnomad FIN AF: 0.766

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.843

Gnomad OTH AF: 0.850

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

GnomAD4 genome AF: 0.856 AC: 130103 AN: 151978 Hom.: 55965 Cov.: 30 AF XY: 0.853 AC XY: 63377 AN XY: 74298

African (AFR) AF: 0.924 AC: 38202 AN: 41332

American (AMR) AF: 0.796 AC: 12171 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.884 AC: 3070 AN: 3472

East Asian (EAS) AF: 0.823 AC: 4262 AN: 5176

South Asian (SAS) AF: 0.843 AC: 4069 AN: 4826

European-Finnish (FIN) AF: 0.766 AC: 8103 AN: 10576

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.843 AC: 57307 AN: 67998

Other (OTH) AF: 0.852 AC: 1797 AN: 2108

Alfa AF: 0.848 Hom.: 131925

Bravo AF: 0.859

Asia WGS AF: 0.837 AC: 2912 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.34
DANN	Benign	0.69
PhyloP100		-0.71
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: rs2631958; hg19: chr2-29958841;