rs4319896

Variant names:

• chr2-29916983-C-A
• rs4319896
• NM_004304.5:c.667+3010G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-29916983-C-A
• chr2-29916983-C-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004304.5(ALK):​c.667+3010G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 152,046 control chromosomes in the GnomAD database, including 16,964 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 0.47 (16964 hom., cov: 33)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.662
• Publications: 7 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000233862 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004304.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	NM_004304.5	MANE Select	c.667+3010G>T		intron	N/A	NP_004295.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.667+3010G>T		intron	N/A	ENSP00000373700.3	Q9UM73
	ENSG00000233862	ENST00000669284.1		n.157+38266G>T		intron	N/A
	ENSG00000233862	ENST00000769926.1		n.534+9236G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71469 AN: 151928 Hom.: 16946 Cov.: 33

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.427

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.416

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.477

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

GnomAD4 genome AF: 0.470 AC: 71527 AN: 152046 Hom.: 16964 Cov.: 33 AF XY: 0.465 AC XY: 34581 AN XY: 74318

African (AFR) AF: 0.499 AC: 20696 AN: 41444

American (AMR) AF: 0.455 AC: 6956 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 1481 AN: 3472

East Asian (EAS) AF: 0.411 AC: 2127 AN: 5174

South Asian (SAS) AF: 0.422 AC: 2031 AN: 4816

European-Finnish (FIN) AF: 0.416 AC: 4391 AN: 10566

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.474 AC: 32248 AN: 67976

Other (OTH) AF: 0.472 AC: 996 AN: 2110

Alfa AF: 0.467 Hom.: 5527

Bravo AF: 0.474

Asia WGS AF: 0.420 AC: 1463 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.9
DANN	Benign	0.34
PhyloP100		0.66
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4319896;

hg19: chr2-30139849;