2-29920310-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004304.5(ALK):​c.350C>A​(p.Pro117Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,406,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ALK
NM_004304.5 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.809
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.22991729).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALKNM_004304.5 linkc.350C>A p.Pro117Gln missense_variant Exon 1 of 29 ENST00000389048.8 NP_004295.2 Q9UM73B6D4Y2
ALKXR_001738688.3 linkn.1277C>A non_coding_transcript_exon_variant Exon 1 of 18

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALKENST00000389048.8 linkc.350C>A p.Pro117Gln missense_variant Exon 1 of 29 1 NM_004304.5 ENSP00000373700.3 Q9UM73
ENSG00000288553ENST00000669284.1 linkn.157+34939C>A intron_variant Intron 1 of 1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000142
AC:
2
AN:
1406902
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
695212
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000184
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 27, 2024This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 117 of the ALK protein (p.Pro117Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ALK-related conditions. 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 tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.026
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
17
DANN
Benign
0.94
DEOGEN2
Benign
0.098
T
Eigen
Benign
0.021
Eigen_PC
Benign
0.0013
FATHMM_MKL
Benign
0.43
N
LIST_S2
Benign
0.46
T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.23
T
MetaSVM
Benign
-0.41
T
MutationAssessor
Benign
0.55
N
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-0.80
N
REVEL
Benign
0.082
Sift
Uncertain
0.0060
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.98
D
Vest4
0.16
MutPred
0.21
Loss of loop (P = 9e-04);
MVP
0.53
MPC
0.32
ClinPred
0.37
T
GERP RS
4.5
Varity_R
0.062
gMVP
0.13

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201290745; hg19: chr2-30143176; API