2-29328351-G-C

Variant names:

• chr2-29328351-G-C
• rs770707805
• NM_004304.5:c.1413C>G

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.1413C>G​(p.Cys471Trp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C471C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALK NM_004304.5 missense, splice_region
• Scores: Splicing: ADA: 0.8881
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.79
• 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

ENSG00000286963 (HGNC:):

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, 0.961

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.1413C>G	p.Cys471Trp	missense_variant, splice_region_variant	Exon 6 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.2340C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 18
LOC101929386	XR_007086263.1	n.447+5823G>C		intron_variant	Intron 3 of 4
LOC101929386	XR_939920.3	n.198-34G>C		intron_variant	Intron 3 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.1413C>G	p.Cys471Trp	missense_variant, splice_region_variant	Exon 6 of 29	1	NM_004304.5	ENSP00000373700.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.75	T;T
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.035	D
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		3.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.7	D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.95
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.68
gMVP		0.93
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.10		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: rs770707805; hg19: chr2-29551217;