rs753646573

Variant names:

• chr2-29717635-T-A
• rs753646573
• NM_004304.5:c.730A>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_004304.5(ALK):​c.730A>T​(p.Asn244Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N244T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.63
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity ALK_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.730A>T	p.Asn244Tyr	missense_variant	Exon 2 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.1657A>T		non_coding_transcript_exon_variant	Exon 2 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.730A>T	p.Asn244Tyr	missense_variant	Exon 2 of 29	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.-402A>T		5_prime_UTR_variant	Exon 1 of 28	5		ENSP00000482733.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251338 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461700 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727170

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111840

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000480 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Uncertain:2

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 244 of the ALK protein (p.Asn244Tyr). This variant is present in population databases (rs753646573, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ALK-related conditions. ClinVar contains an entry for this variant (Variation ID: 404332). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jun 17, 2025

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ALK c.730A>T (p.Asn244Tyr) missense change has a maximum subpopulation frequency of 0.0086% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but t o our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with ALK-related neuroblastic tumor susceptibility. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N244Y variant (also known as c.730A>T), located in coding exon 2 of the ALK gene, results from an A to T substitution at nucleotide position 730. The asparagine at codon 244 is replaced by tyrosine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.55	N
PhyloP100		4.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.36		Loss of catalytic residue at N244 (P = 0.1278);
MVP		0.90
MPC		0.78
ClinPred		0.87	D
GERP RS		5.0
PromoterAI		-0.018	Neutral
Varity_R		0.22
gMVP		0.67
Mutation Taster		=72/28	polymorphism

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: rs753646573; hg19: chr2-29940501;