2-29232401-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004304.5(ALK):c.2535T>C(p.Gly845Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 1,614,012 control chromosomes in the GnomAD database, including 370,500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G845G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.62 ( 30945 hom., cov: 34)

Exomes 𝑓: 0.67 ( 339555 hom. )

Consequence

ALK
NM_004304.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.0970

Publications

29 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ALK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 2-29232401-A-G is Benign according to our data. Variant chr2-29232401-A-G is described in ClinVar as Benign. ClinVar VariationId is 259268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.097 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004304.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	NM_004304.5	MANE Select	c.2535T>C	p.Gly845Gly	synonymous	Exon 15 of 29	NP_004295.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.2535T>C	p.Gly845Gly	synonymous	Exon 15 of 29	ENSP00000373700.3	Q9UM73
	ALK	ENST00000618119.4	TSL:5	c.1404T>C	p.Gly468Gly	synonymous	Exon 14 of 28	ENSP00000482733.1	A0A087WZL3

Frequencies

GnomAD3 genomes

AF:

0.625

AC:

95012

AN:

152066

Hom.:

30941

Cov.:

show subpopulations

Gnomad AFR

AF:

0.542

Gnomad AMI

AF:

0.603

Gnomad AMR

AF:

0.562

Gnomad ASJ

AF:

0.799

Gnomad EAS

AF:

0.182

Gnomad SAS

AF:

0.574

Gnomad FIN

AF:

0.660

Gnomad MID

AF:

0.782

Gnomad NFE

AF:

0.711

Gnomad OTH

AF:

0.664

GnomAD2 exomes

AF:

0.607

AC:

152696

AN:

251414

AF XY:

0.621

show subpopulations

Gnomad AFR exome

AF:

0.541

Gnomad AMR exome

AF:

0.445

Gnomad ASJ exome

AF:

0.800

Gnomad EAS exome

AF:

0.177

Gnomad FIN exome

AF:

0.651

Gnomad NFE exome

AF:

0.710

Gnomad OTH exome

AF:

0.661

GnomAD4 exome

AF:

0.673

AC:

983411

AN:

1461828

Hom.:

339555

Cov.:

AF XY:

0.674

AC XY:

489984

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.543

AC:

18188

AN:

33480

American (AMR)

AF:

0.461

AC:

20603

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.795

AC:

20788

AN:

26136

East Asian (EAS)

AF:

0.170

AC:

6766

AN:

39700

South Asian (SAS)

AF:

0.602

AC:

51933

AN:

86252

European-Finnish (FIN)

AF:

0.652

AC:

34811

AN:

53414

Middle Eastern (MID)

AF:

0.771

AC:

4449

AN:

5768

European-Non Finnish (NFE)

AF:

0.707

AC:

785819

AN:

1111966

Other (OTH)

AF:

0.663

AC:

40054

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

19052

38104

57155

76207

95259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19466

38932

58398

77864

97330

<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:

0.624

AC:

95033

AN:

152184

Hom.:

30945

Cov.:

AF XY:

0.616

AC XY:

45837

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.542

AC:

22479

AN:

41512

American (AMR)

AF:

0.562

AC:

8598

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.799

AC:

2772

AN:

3470

East Asian (EAS)

AF:

0.181

AC:

936

AN:

5174

South Asian (SAS)

AF:

0.575

AC:

2776

AN:

4826

European-Finnish (FIN)

AF:

0.660

AC:

6984

AN:

10582

Middle Eastern (MID)

AF:

0.796

AC:

234

AN:

294

European-Non Finnish (NFE)

AF:

0.711

AC:

48319

AN:

68006

Other (OTH)

AF:

0.656

AC:

1385

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1760

3519

5279

7038

8798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

766

1532

2298

3064

3830

<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:

0.679

Hom.:

77025

Bravo

AF:

0.614

Asia WGS

AF:

0.370

AC:

1288

AN:

3478

EpiCase

AF:

0.724

EpiControl

AF:

0.726

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neuroblastoma, susceptibility to, 3 (6)

not provided (2)

not specified (2)

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.38

(source)

DANN

Benign

0.69

PhyloP100

-0.097

Mutation Taster

=93/7

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over