2-29462730-C-T

Position:

• chr2-29462730-C-T

Variant summary

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

The NM_004304.5(ALK):​c.1154+69185G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 152,082 control chromosomes in the GnomAD database, including 2,159 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 0.16 (2159 hom., cov: 33)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.60

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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5	c.1154+69185G>A		intron_variant		ENST00000389048.8
ALK	XR_001738688.3	n.2081+69185G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.1154+69185G>A		intron_variant		1	NM_004304.5	P1
ALK	ENST00000618119.4	c.23+69185G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24181 AN: 151964 Hom.: 2154 Cov.: 33

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.0862

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.159

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

GnomAD4 genome AF: 0.159 AC: 24197 AN: 152082 Hom.: 2159 Cov.: 33 AF XY: 0.162 AC XY: 12078 AN XY: 74338

Gnomad4 AFR AF: 0.140

Gnomad4 AMR AF: 0.180

Gnomad4 ASJ AF: 0.0862

Gnomad4 EAS AF: 0.352

Gnomad4 SAS AF: 0.274

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.161

Alfa AF: 0.145 Hom.: 3051

Bravo AF: 0.161

Asia WGS AF: 0.259 AC: 903 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.018
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3923028; hg19: chr2-29685596;