rs2254066

chr2-29666153-C-Achr2-29666153-C-G

Variant summary

Our verdict is Benign. Variant got -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

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 -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/exons	MANE	UniProt
ALK	NM_004304.5	c.952+28697G>T		intron_variant		ENST00000389048.8
ALK	XR_001738688.3	n.1879+28697G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.952+28697G>T		intron_variant		1	NM_004304.5	P1
ALK	ENST00000618119.4	c.-180+28697G>T		intron_variant		5

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

Gnomad4 AFR AF: 0.937

Gnomad4 AMR AF: 0.798

Gnomad4 ASJ AF: 0.882

Gnomad4 EAS AF: 0.769

Gnomad4 SAS AF: 0.858

Gnomad4 FIN AF: 0.753

Gnomad4 NFE AF: 0.831

Gnomad4 OTH AF: 0.848

Alfa AF: 0.842 Hom.: 54539

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

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: rs2254066; hg19: chr2-29889019; COSMIC: COSV66594889;