rs11683248

Variant names:

• chr2-29225980-C-G
• rs11683248
• NM_004304.5:c.3068-415G>C

Variant summary

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

The NM_004304.5(ALK):​c.3068-415G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 151,836 control chromosomes in the GnomAD database, including 9,273 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 0.34 (9273 hom., cov: 30)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.473
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.3068-415G>C		intron_variant	Intron 18 of 28	ENST00000389048.8	NP_004295.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.3068-415G>C		intron_variant	Intron 18 of 28	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.1937-415G>C		intron_variant	Intron 17 of 27	5		ENSP00000482733.1
ALK	ENST00000431873.6	n.233-415G>C		intron_variant	Intron 2 of 13	5		ENSP00000414027.3

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51267 AN: 151718 Hom.: 9254 Cov.: 30

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.0429

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.321

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

GnomAD4 genome AF: 0.338 AC: 51296 AN: 151836 Hom.: 9273 Cov.: 30 AF XY: 0.336 AC XY: 24927 AN XY: 74186

African (AFR) AF: 0.307 AC: 12697 AN: 41386

American (AMR) AF: 0.228 AC: 3473 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1350 AN: 3472

East Asian (EAS) AF: 0.0426 AC: 220 AN: 5168

South Asian (SAS) AF: 0.333 AC: 1595 AN: 4796

European-Finnish (FIN) AF: 0.455 AC: 4789 AN: 10536

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26150 AN: 67904

Other (OTH) AF: 0.317 AC: 666 AN: 2104

Alfa AF: 0.367 Hom.: 1353

Bravo AF: 0.317

Asia WGS AF: 0.165 AC: 574 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.2
DANN	Benign	0.33
PhyloP100		-0.47
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: rs11683248; hg19: chr2-29448846;