2-29214054-C-T

Position:

• chr2-29214054-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004304.5(ALK):​c.3673G>A​(p.Asp1225Asn) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALK	NM_004304.5	c.3673G>A	p.Asp1225Asn	missense_variant	24/29	ENST00000389048.8	NP_004295.2
ALK	NM_001353765.2	c.469G>A	p.Asp157Asn	missense_variant	5/10		NP_001340694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.3673G>A	p.Asp1225Asn	missense_variant	24/29	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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2020

The p.D1225N variant (also known as c.3673G>A), located in coding exon 24 of the ALK gene, results from a G to A substitution at nucleotide position 3673. The aspartic acid at codon 1225 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	0.42
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.075	T;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.1	.;L;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.8	.;D;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	.;D;.
Sift4G	Uncertain	0.010	.;D;D
Polyphen		1.0	.;D;.
Vest4		0.91, 0.86
MutPred		0.68		.;Loss of phosphorylation at S1220 (P = 0.1638);.;
MVP		0.90
MPC		0.69
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.89
gMVP		0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519696; hg19: chr2-29436920; COSMIC: COSV66559339;