rs11685486

Variant names:

• chr2-29428164-C-T
• rs11685486
• NM_004304.5:c.1155-44305G>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.1155-44305G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 151,836 control chromosomes in the GnomAD database, including 1,552 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 0.12 (1552 hom., cov: 33)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.352
• 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=-1.04).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.1155-44305G>A		intron_variant	Intron 4 of 28	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.2082-44305G>A		intron_variant	Intron 4 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.1155-44305G>A		intron_variant	Intron 4 of 28	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.24-44305G>A		intron_variant	Intron 3 of 27	5		ENSP00000482733.1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18606 AN: 151718 Hom.: 1549 Cov.: 33

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.0505

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.0976

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.0528

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0727

Gnomad OTH AF: 0.122

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

GnomAD4 genome AF: 0.123 AC: 18625 AN: 151836 Hom.: 1552 Cov.: 33 AF XY: 0.125 AC XY: 9294 AN XY: 74204

African (AFR) AF: 0.175 AC: 7236 AN: 41454

American (AMR) AF: 0.198 AC: 3014 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0976 AC: 338 AN: 3464

East Asian (EAS) AF: 0.307 AC: 1587 AN: 5172

South Asian (SAS) AF: 0.131 AC: 632 AN: 4820

European-Finnish (FIN) AF: 0.0528 AC: 557 AN: 10540

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0727 AC: 4932 AN: 67822

Other (OTH) AF: 0.121 AC: 254 AN: 2102

Alfa AF: 0.0859 Hom.: 347

Bravo AF: 0.135

Asia WGS AF: 0.218 AC: 755 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.7
DANN	Benign	0.64
PhyloP100		-0.35
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: rs11685486; hg19: chr2-29651030;