NM_004304.5:c.1647+66G>A

Variant names:

• chr2-29318238-C-T
• rs2276549
• NM_004304.5:c.1647+66G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004304.5(ALK):​c.1647+66G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 1,348,214 control chromosomes in the GnomAD database, including 311,652 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (28426 hom., cov: 32)
  • Exomes 𝑓: 0.68 (283226 hom.)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.278
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-29318238-C-T is Benign according to our data. Variant chr2-29318238-C-T is described in ClinVar as Benign. ClinVar VariationId is 676804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.1647+66G>A		intron_variant	Intron 8 of 28	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.2574+66G>A		intron_variant	Intron 8 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.1647+66G>A		intron_variant	Intron 8 of 28	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.516+66G>A		intron_variant	Intron 7 of 27	5		ENSP00000482733.1
ALK	ENST00000498037.1	n.202+66G>A		intron_variant	Intron 2 of 4	4

Frequencies

GnomAD3 genomes AF: 0.573 AC: 86973 AN: 151900 Hom.: 28418 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.693

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.754

Gnomad FIN AF: 0.724

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.692

Gnomad OTH AF: 0.591

GnomAD4 exome AF: 0.682 AC: 816378 AN: 1196196 Hom.: 283226 AF XY: 0.686 AC XY: 416225 AN XY: 606878

African (AFR) AF: 0.215 AC: 6095 AN: 28294

American (AMR) AF: 0.769 AC: 33209 AN: 43190

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 16147 AN: 24440

East Asian (EAS) AF: 0.809 AC: 31008 AN: 38312

South Asian (SAS) AF: 0.746 AC: 59328 AN: 79576

European-Finnish (FIN) AF: 0.713 AC: 37683 AN: 52822

Middle Eastern (MID) AF: 0.645 AC: 3374 AN: 5232

European-Non Finnish (NFE) AF: 0.682 AC: 595238 AN: 872584

Other (OTH) AF: 0.663 AC: 34296 AN: 51746

GnomAD4 genome AF: 0.572 AC: 86995 AN: 152018 Hom.: 28426 Cov.: 32 AF XY: 0.580 AC XY: 43108 AN XY: 74268

African (AFR) AF: 0.232 AC: 9624 AN: 41458

American (AMR) AF: 0.694 AC: 10606 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 2293 AN: 3468

East Asian (EAS) AF: 0.803 AC: 4150 AN: 5168

South Asian (SAS) AF: 0.755 AC: 3628 AN: 4806

European-Finnish (FIN) AF: 0.724 AC: 7634 AN: 10546

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.692 AC: 47025 AN: 67982

Other (OTH) AF: 0.590 AC: 1243 AN: 2106

Alfa AF: 0.587 Hom.: 22267

Bravo AF: 0.552

Asia WGS AF: 0.715 AC: 2486 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.8
DANN	Benign	0.64
PhyloP100		0.28
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: rs2276549; hg19: chr2-29541104;