2-29920271-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004304.5(ALK):c.389G>T(p.Gly130Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,441,614 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G130S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ALK
NM_004304.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.15

Publications

0 publications found

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]

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

ALK links:

ENSG00000233862 (HGNC:):

ENSG00000233862 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5 link	c.389G>T	p.Gly130Val	missense_variant	Exon 1 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3 link	n.1316G>T		non_coding_transcript_exon_variant	Exon 1 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ALK	ENST00000389048.8 link	c.389G>T	p.Gly130Val	missense_variant	Exon 1 of 29	1	NM_004304.5	ENSP00000373700.3
ENSG00000233862	ENST00000669284.1 link	n.157+34978G>T		intron_variant	Intron 1 of 1
ENSG00000233862	ENST00000769926.1 link	n.534+5948G>T		intron_variant	Intron 4 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441614

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715764

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33126

American (AMR)

AF:

0.00

AC:

AN:

41556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25716

East Asian (EAS)

AF:

0.00

AC:

AN:

38798

South Asian (SAS)

AF:

0.00

AC:

AN:

84120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49704

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103208

Other (OTH)

AF:

0.00

AC:

AN:

59660

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3

Uncertain:1

Nov 03, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals with ALK-related disease. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 130 of the ALK protein (p.Gly130Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G130V variant (also known as c.389G>T), located in coding exon 1 of the ALK gene, results from a G to T substitution at nucleotide position 389. The glycine at codon 130 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

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.73

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.48

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

0.69

PhyloP100

5.2

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.4

REVEL

Benign

0.16

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.42

MutPred

0.35

Loss of helix (P = 0.0167);

MVP

0.80

MPC

0.79

ClinPred

0.91

GERP RS

5.3

Varity_R

0.49

gMVP

0.45

Mutation Taster

=40/60

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over