2-29228940-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_004304.5(ALK):c.2759G>A(p.Gly920Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 841,172 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G920S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000041 ( 0 hom., cov: 23)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

ALK
NM_004304.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.35

Publications

2 publications found

Variant links:

COSMIC-nc: COSV66588513

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.876

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5 link	c.2759G>A	p.Gly920Asp	missense_variant	Exon 16 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3 link	n.3668+18G>A		intron_variant	Intron 16 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8 link	c.2759G>A	p.Gly920Asp	missense_variant	Exon 16 of 29	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4 link	c.1628G>A	p.Gly543Asp	missense_variant	Exon 15 of 28	5		ENSP00000482733.1

Frequencies

GnomAD3 genomes

AF:

0.0000406

AC:

AN:

98554

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:

0.0000847

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000123

AC:

AN:

243688

AF XY:

0.00000757

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.0000148

AC:

AN:

742618

Hom.:

Cov.:

AF XY:

0.0000160

AC XY:

AN XY:

375986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17586

American (AMR)

AF:

0.00

AC:

AN:

26328

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15430

East Asian (EAS)

AF:

0.00

AC:

AN:

24388

South Asian (SAS)

AF:

0.00

AC:

AN:

52534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3700

European-Non Finnish (NFE)

AF:

0.0000205

AC:

AN:

536206

Other (OTH)

AF:

0.00

AC:

AN:

30858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.593

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000406

AC:

AN:

98554

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

47870

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26074

American (AMR)

AF:

0.00

AC:

AN:

8626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2428

East Asian (EAS)

AF:

0.00

AC:

AN:

3482

South Asian (SAS)

AF:

0.00

AC:

AN:

3162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000847

AC:

AN:

47214

Other (OTH)

AF:

0.00

AC:

AN:

1280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.588

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000261

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3

Uncertain:2

Dec 29, 2023

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 920 of the ALK protein (p.Gly920Asp). This variant is present in population databases (rs746643773, gnomAD 0.0009%). 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: 470804). 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. 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

Uncertain:1

Jun 05, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome

Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G920D variant (also known as c.2759G>A), located in coding exon 16 of the ALK gene, results from a G to A substitution at nucleotide position 2759. The glycine at codon 920 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.83

T;T

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.7

H;.

PhyloP100

7.4

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-4.7

D;.

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0020

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.84

MutPred

0.52

Loss of MoRF binding (P = 0.048);.;

MVP

0.76

MPC

0.81

ClinPred

1.0

GERP RS

5.2

Varity_R

0.83

gMVP

0.91

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over