rs11683248

Positions:

• chr2-29225980-C-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ALK	NM_004304.5	c.3068-415G>C		intron_variant		ENST00000389048.8	NP_004295.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.3068-415G>C		intron_variant		1	NM_004304.5	ENSP00000373700	P1
ALK	ENST00000618119.4	c.1937-415G>C		intron_variant		5		ENSP00000482733
ALK	ENST00000431873.6	c.234-415G>C		intron_variant, NMD_transcript_variant		5		ENSP00000414027

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

Gnomad4 AFR AF: 0.307

Gnomad4 AMR AF: 0.228

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.0426

Gnomad4 SAS AF: 0.333

Gnomad4 FIN AF: 0.455

Gnomad4 NFE AF: 0.385

Gnomad4 OTH AF: 0.317

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs11683248; hg19: chr2-29448846;