2-29209873-A-G

Position:

chr2-29209873-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_004304.5(ALK):c.3749T>C(p.Ile1250Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ALK
NM_004304.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3O:1

Conservation

PhyloP100: 9.32

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 links:

ALK (HGNC:):

ALK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALK	NM_004304.5 linkuse as main transcript	c.3749T>C	p.Ile1250Thr	missense_variant	25/29	ENST00000389048.8	NP_004295.2	Q9UM73B6D4Y2
ALK	NM_001353765.2 linkuse as main transcript	c.545T>C	p.Ile182Thr	missense_variant	6/10		NP_001340694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8 linkuse as main transcript	c.3749T>C	p.Ile1250Thr	missense_variant	25/29	1	NM_004304.5	ENSP00000373700.3		Q9UM73

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251336

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135820

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461684

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727174

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

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:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3

Uncertain:2Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 21, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2023	Experimental studies have shown that this missense change affects ALK function (PMID: 21804922, 25517749). 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 21867). This missense change has been observed in individual(s) with neuroblastoma (PMID: 18724359). This variant is present in population databases (rs113994092, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1250 of the ALK protein (p.Ile1250Thr). 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. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2023

The p.I1250T variant (also known as c.3749T>C), located in coding exon 25 of the ALK gene, results from a T to C substitution at nucleotide position 3749. The isoleucine at codon 1250 is replaced by threonine, an amino acid with similar properties. This alteration was observed in the germline of a individual with neuroblastoma who had at least one other relative with neuroblastoma; however, this alteration has also been observed in unaffected individuals (Mossé YP et al. Nature, 2008 Oct;455:930-5; Ambry internal data). Functional studies demonstrate that p.I1250T is inactivating and has the potential to act as a dominant-negative receptor; however, its association with disease is unclear (Schönherr C et al. Transl Oncol, 2011 Aug;4:258-65; Bresler SC et al. Cancer Cell, 2014 Nov;26:682-94; Ma Y et al. Oncogene, 2016 11;35:6132-6142). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;D;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

D;D;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.6

.;M;.

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-4.9

.;D;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0010

.;D;D

Polyphen

1.0

.;D;.

Vest4

0.97, 0.97

MutPred

0.83

.;Gain of phosphorylation at I1250 (P = 0.0982);.;

MVP

0.96

MPC

0.79

ClinPred

1.0

GERP RS

5.2

Varity_R

0.98

gMVP

0.94

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over