rs2254066

Variant names:

• chr2-29666153-C-A
• rs2254066
• NM_004304.5:c.952+28697G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-29666153-C-A
• chr2-29666153-C-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_004304.5(ALK):​c.952+28697G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.852 in 152,120 control chromosomes in the GnomAD database, including 55,546 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 0.85 (55546 hom., cov: 31)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11
• Publications: 4 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.952+28697G>T		intron_variant	Intron 3 of 28	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.1879+28697G>T		intron_variant	Intron 3 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.952+28697G>T		intron_variant	Intron 3 of 28	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.-180+28697G>T		intron_variant	Intron 2 of 27	5		ENSP00000482733.1

Frequencies

GnomAD3 genomes AF: 0.852 AC: 129519 AN: 152002 Hom.: 55488 Cov.: 31

Gnomad AFR AF: 0.937

Gnomad AMI AF: 0.949

Gnomad AMR AF: 0.798

Gnomad ASJ AF: 0.882

Gnomad EAS AF: 0.770

Gnomad SAS AF: 0.858

Gnomad FIN AF: 0.753

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.831

Gnomad OTH AF: 0.846

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

GnomAD4 genome AF: 0.852 AC: 129636 AN: 152120 Hom.: 55546 Cov.: 31 AF XY: 0.849 AC XY: 63124 AN XY: 74358

African (AFR) AF: 0.937 AC: 38916 AN: 41536

American (AMR) AF: 0.798 AC: 12184 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 3058 AN: 3468

East Asian (EAS) AF: 0.769 AC: 3965 AN: 5154

South Asian (SAS) AF: 0.858 AC: 4143 AN: 4826

European-Finnish (FIN) AF: 0.753 AC: 7959 AN: 10566

Middle Eastern (MID) AF: 0.840 AC: 247 AN: 294

European-Non Finnish (NFE) AF: 0.831 AC: 56510 AN: 67992

Other (OTH) AF: 0.848 AC: 1790 AN: 2112

Alfa AF: 0.843 Hom.: 71034

Bravo AF: 0.857

Asia WGS AF: 0.837 AC: 2910 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Benign	0.74
PhyloP100		2.1
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: rs2254066; hg19: chr2-29889019; COSMIC: COSV66594889;