2-29856091-T-C

Variant names:

• chr2-29856091-T-C
• rs4581855
• NM_004304.5:c.667+63902A>G

Variant summary

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

The NM_004304.5(ALK):​c.667+63902A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.72 in 151,992 control chromosomes in the GnomAD database, including 39,941 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 0.72 (39941 hom., cov: 31)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.191
• Publications: 6 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

ENSG00000233862 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.667+63902A>G		intron_variant	Intron 1 of 28	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.1594+63902A>G		intron_variant	Intron 1 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.667+63902A>G		intron_variant	Intron 1 of 28	1	NM_004304.5	ENSP00000373700.3
ENSG00000233862	ENST00000669284.1	n.158-14454A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109366 AN: 151874 Hom.: 39912 Cov.: 31

Gnomad AFR AF: 0.610

Gnomad AMI AF: 0.882

Gnomad AMR AF: 0.730

Gnomad ASJ AF: 0.735

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.785

Gnomad MID AF: 0.669

Gnomad NFE AF: 0.784

Gnomad OTH AF: 0.717

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

GnomAD4 genome AF: 0.720 AC: 109443 AN: 151992 Hom.: 39941 Cov.: 31 AF XY: 0.720 AC XY: 53500 AN XY: 74276

African (AFR) AF: 0.610 AC: 25291 AN: 41462

American (AMR) AF: 0.730 AC: 11127 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.735 AC: 2548 AN: 3466

East Asian (EAS) AF: 0.671 AC: 3467 AN: 5170

South Asian (SAS) AF: 0.601 AC: 2875 AN: 4786

European-Finnish (FIN) AF: 0.785 AC: 8305 AN: 10580

Middle Eastern (MID) AF: 0.678 AC: 198 AN: 292

European-Non Finnish (NFE) AF: 0.784 AC: 53313 AN: 67970

Other (OTH) AF: 0.719 AC: 1515 AN: 2106

Alfa AF: 0.758 Hom.: 136431

Bravo AF: 0.713

Asia WGS AF: 0.638 AC: 2217 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	11
DANN	Benign	0.56
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4581855; hg19: chr2-30078957;