chr2-29209816-C-A

Variant names:

• chr2-29209816-C-A
• rs1057519781
• NM_004304.5:c.3806G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004304.5(ALK):​c.3806G>T​(p.Gly1269Val) variant causes a missense 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. 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. G1269R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90
• 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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.3806G>T	p.Gly1269Val	missense_variant	Exon 25 of 29	ENST00000389048.8	NP_004295.2
ALK	NM_001353765.2	c.602G>T	p.Gly201Val	missense_variant	Exon 6 of 10		NP_001340694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.3806G>T	p.Gly1269Val	missense_variant	Exon 25 of 29	1	NM_004304.5	ENSP00000373700.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

May 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G1269V variant (also known as c.3806G>T), located in coding exon 25 of the ALK gene, results from a G to T substitution at nucleotide position 3806. The glycine at codon 1269 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.5	.;L;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-8.9	.;D;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	.;D;.
Sift4G	Uncertain	0.0030	.;D;D
Polyphen		1.0	.;D;.
Vest4		0.96
MutPred		0.82		.;Gain of ubiquitination at K1267 (P = 0.0619);.;
MVP		0.94
MPC		0.79
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.95
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057519781; hg19: chr2-29432682;