rs6754181

Variant names:

• chr2-29743514-T-C
• rs6754181
• NM_004304.5:c.668-25817A>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.668-25817A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.858 in 152,244 control chromosomes in the GnomAD database, including 56,245 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 (56245 hom., cov: 33)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.72
• Publications: 1 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=-0.96).
• 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.668-25817A>G		intron_variant	Intron 1 of 28	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.1595-25817A>G		intron_variant	Intron 1 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.668-25817A>G		intron_variant	Intron 1 of 28	1	NM_004304.5	ENSP00000373700.3

Frequencies

GnomAD3 genomes AF: 0.858 AC: 130477 AN: 152126 Hom.: 56186 Cov.: 33

Gnomad AFR AF: 0.925

Gnomad AMI AF: 0.951

Gnomad AMR AF: 0.805

Gnomad ASJ AF: 0.886

Gnomad EAS AF: 0.829

Gnomad SAS AF: 0.836

Gnomad FIN AF: 0.766

Gnomad MID AF: 0.866

Gnomad NFE AF: 0.844

Gnomad OTH AF: 0.849

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

GnomAD4 genome AF: 0.858 AC: 130593 AN: 152244 Hom.: 56245 Cov.: 33 AF XY: 0.855 AC XY: 63616 AN XY: 74432

African (AFR) AF: 0.925 AC: 38436 AN: 41548

American (AMR) AF: 0.805 AC: 12319 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 3077 AN: 3472

East Asian (EAS) AF: 0.829 AC: 4293 AN: 5178

South Asian (SAS) AF: 0.837 AC: 4038 AN: 4826

European-Finnish (FIN) AF: 0.766 AC: 8117 AN: 10598

Middle Eastern (MID) AF: 0.870 AC: 254 AN: 292

European-Non Finnish (NFE) AF: 0.844 AC: 57395 AN: 68012

Other (OTH) AF: 0.851 AC: 1797 AN: 2112

Alfa AF: 0.851 Hom.: 100973

Bravo AF: 0.862

Asia WGS AF: 0.835 AC: 2906 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.013
DANN	Benign	0.26
PhyloP100		-4.7
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: rs6754181; hg19: chr2-29966380;