2-29462730-C-T

Variant names:

• chr2-29462730-C-T
• rs3923028
• NM_004304.5:c.1154+69185G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 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=-0.97).
• 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 rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.1154+69185G>A		intron_variant	Intron 4 of 28	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.2081+69185G>A		intron_variant	Intron 4 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.1154+69185G>A		intron_variant	Intron 4 of 28	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.23+69185G>A		intron_variant	Intron 3 of 27	5		ENSP00000482733.1

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

African (AFR) AF: 0.140 AC: 5818 AN: 41502

American (AMR) AF: 0.180 AC: 2753 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0862 AC: 299 AN: 3468

East Asian (EAS) AF: 0.352 AC: 1819 AN: 5174

South Asian (SAS) AF: 0.274 AC: 1318 AN: 4818

European-Finnish (FIN) AF: 0.157 AC: 1663 AN: 10564

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 10007 AN: 67960

Other (OTH) AF: 0.161 AC: 339 AN: 2108

Alfa AF: 0.148 Hom.: 5036

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
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3923028; hg19: chr2-29685596;