rs368059424

Variant names:

• chr2-29213984-C-A
• rs368059424
• NM_004304.5:c.3743G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-29213984-C-A
• chr2-29213984-C-G
• chr2-29213984-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_004304.5(ALK):​c.3743G>T​(p.Arg1248Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 15/26 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1248Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALK NM_004304.5 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 22 uncertain in NM_004304.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.3743G>T	p.Arg1248Leu	missense_variant, splice_region_variant	Exon 24 of 29	ENST00000389048.8	NP_004295.2
ALK	NM_001353765.2	c.539G>T	p.Arg180Leu	missense_variant, splice_region_variant	Exon 5 of 10		NP_001340694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.3743G>T	p.Arg1248Leu	missense_variant, splice_region_variant	Exon 24 of 29	1	NM_004304.5	ENSP00000373700.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;D;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.2	.;M;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-6.9	.;D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0010	.;D;D
Polyphen		1.0	.;D;.
Vest4		0.99, 0.99
MutPred		0.85		.;Gain of sheet (P = 0.0827);.;
MVP		0.97
MPC		0.79
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.96
gMVP		0.96
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.53		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs368059424; hg19: chr2-29436850; COSMIC: COSV101201819;