rs1073319

Positions:

• chr2-29217588-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004304.5(ALK):​c.3645+3118C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 152,106 control chromosomes in the GnomAD database, including 6,197 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 0.25 (6197 hom., cov: 32)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.294

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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALK	NM_004304.5	c.3645+3118C>T		intron_variant		ENST00000389048.8	NP_004295.2
ALK	NM_001353765.2	c.441+3118C>T		intron_variant			NP_001340694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.3645+3118C>T		intron_variant		1	NM_004304.5	ENSP00000373700	P1

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38017 AN: 151988 Hom.: 6184 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.728

Gnomad SAS AF: 0.414

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.254

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

GnomAD4 genome AF: 0.250 AC: 38054 AN: 152106 Hom.: 6197 Cov.: 32 AF XY: 0.264 AC XY: 19607 AN XY: 74350

Gnomad4 AFR AF: 0.156

Gnomad4 AMR AF: 0.416

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.729

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.322

Gnomad4 NFE AF: 0.213

Gnomad4 OTH AF: 0.260

Alfa AF: 0.0792 Hom.: 124

Bravo AF: 0.258

Asia WGS AF: 0.559 AC: 1941 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.9
DANN	Benign	0.68

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: rs1073319; hg19: chr2-29440454;