2-29310479-C-T

Variant names:

• chr2-29310479-C-T
• rs6750752
• NM_004304.5:c.1647+7825G>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.1647+7825G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.726 in 152,096 control chromosomes in the GnomAD database, including 41,289 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 0.73 (41289 hom., cov: 32)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0370
• Publications: 4 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.802 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.1647+7825G>A		intron_variant	Intron 8 of 28	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.2574+7825G>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+7825G>A		intron_variant	Intron 8 of 28	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.516+7825G>A		intron_variant	Intron 7 of 27	5		ENSP00000482733.1
ALK	ENST00000498037.1	n.202+7825G>A		intron_variant	Intron 2 of 4	4

Frequencies

GnomAD3 genomes AF: 0.726 AC: 110335 AN: 151978 Hom.: 41268 Cov.: 32

Gnomad AFR AF: 0.522

Gnomad AMI AF: 0.839

Gnomad AMR AF: 0.802

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.793

Gnomad SAS AF: 0.769

Gnomad FIN AF: 0.823

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.807

Gnomad OTH AF: 0.729

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

GnomAD4 genome AF: 0.726 AC: 110386 AN: 152096 Hom.: 41289 Cov.: 32 AF XY: 0.729 AC XY: 54180 AN XY: 74350

African (AFR) AF: 0.521 AC: 21596 AN: 41438

American (AMR) AF: 0.802 AC: 12257 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 2584 AN: 3470

East Asian (EAS) AF: 0.793 AC: 4115 AN: 5188

South Asian (SAS) AF: 0.770 AC: 3709 AN: 4816

European-Finnish (FIN) AF: 0.823 AC: 8712 AN: 10580

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.807 AC: 54892 AN: 68006

Other (OTH) AF: 0.727 AC: 1532 AN: 2108

Alfa AF: 0.782 Hom.: 76732

Bravo AF: 0.713

Asia WGS AF: 0.756 AC: 2629 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.2
DANN	Benign	0.66
PhyloP100		0.037
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: rs6750752; hg19: chr2-29533345;