2-29920416-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004304.5(ALK):​c.244G>A​(p.Ala82Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000439 in 1,595,174 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A82G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

ALK
NM_004304.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.575
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.062185884).
BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ALKNM_004304.5 linkuse as main transcriptc.244G>A p.Ala82Thr missense_variant 1/29 ENST00000389048.8
ALKXR_001738688.3 linkuse as main transcriptn.1171G>A non_coding_transcript_exon_variant 1/18

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ALKENST00000389048.8 linkuse as main transcriptc.244G>A p.Ala82Thr missense_variant 1/291 NM_004304.5 P1
ENST00000669284.1 linkuse as main transcriptn.157+34833G>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152218
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000944
AC:
2
AN:
211974
Hom.:
0
AF XY:
0.00000867
AC XY:
1
AN XY:
115320
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000219
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000416
AC:
6
AN:
1442956
Hom.:
0
Cov.:
31
AF XY:
0.00000559
AC XY:
4
AN XY:
715976
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:
0.0000196
Gnomad4 NFE exome
AF:
0.00000363
Gnomad4 OTH exome
AF:
0.0000168
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152218
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000111
Hom.:
0

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 testingInvitaeJan 28, 2024This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 82 of the ALK protein (p.Ala82Thr). This variant is present in population databases (no rsID available, gnomAD 0.004%). 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: 538205). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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
0.073
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
8.8
DANN
Uncertain
0.99
DEOGEN2
Benign
0.098
T
Eigen
Benign
-0.91
Eigen_PC
Benign
-0.91
FATHMM_MKL
Benign
0.096
N
LIST_S2
Benign
0.52
T
M_CAP
Benign
0.057
D
MetaRNN
Benign
0.062
T
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
0.69
N
MutationTaster
Benign
0.66
N;N
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-0.36
N
REVEL
Benign
0.035
Sift
Benign
0.12
T
Sift4G
Uncertain
0.032
D
Polyphen
0.0
B
Vest4
0.021
MutPred
0.15
Gain of phosphorylation at A82 (P = 0.018);
MVP
0.50
MPC
0.16
ClinPred
0.089
T
GERP RS
1.9
Varity_R
0.052
gMVP
0.073

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: rs1322397265; hg19: chr2-30143282; API