2-29223336-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004304.5(ALK):c.3359+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,613,208 control chromosomes in the GnomAD database, including 91,119 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 6046 hom., cov: 32)

Exomes 𝑓: 0.33 ( 85073 hom. )

Consequence

ALK
NM_004304.5 splice_region, intron

Scores

Splicing: ADA: 0.00005905

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.20

Publications

11 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 2-29223336-G-A is Benign according to our data. Variant chr2-29223336-G-A is described in ClinVar as Benign. ClinVar VariationId is 259271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.35 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	NM_004304.5	MANE Select	c.3359+6C>T		splice_region intron	N/A	NP_004295.2
	ALK	NM_001353765.2		c.155+6C>T		splice_region intron	N/A	NP_001340694.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ALK	ENST00000389048.8	TSL:1 MANE Select	c.3359+6C>T	splice_region intron	N/A	ENSP00000373700.3
ALK	ENST00000638605.1	TSL:1	n.236+6C>T	splice_region intron	N/A
ALK	ENST00000618119.4	TSL:5	c.2228+6C>T	splice_region intron	N/A	ENSP00000482733.1

Frequencies

GnomAD3 genomes

AF:

0.246

AC:

37338

AN:

152028

Hom.:

6039

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0628

Gnomad AMI

AF:

0.180

Gnomad AMR

AF:

0.198

Gnomad ASJ

AF:

0.374

Gnomad EAS

AF:

0.0404

Gnomad SAS

AF:

0.349

Gnomad FIN

AF:

0.348

Gnomad MID

AF:

0.334

Gnomad NFE

AF:

0.354

Gnomad OTH

AF:

0.256

GnomAD2 exomes

AF:

0.285

AC:

71325

AN:

250108

AF XY:

0.301

show subpopulations

Gnomad AFR exome

AF:

0.0547

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.380

Gnomad EAS exome

AF:

0.0376

Gnomad FIN exome

AF:

0.352

Gnomad NFE exome

AF:

0.354

Gnomad OTH exome

AF:

0.300

GnomAD4 exome

AF:

0.331

AC:

483731

AN:

1461062

Hom.:

85073

Cov.:

AF XY:

0.334

AC XY:

242802

AN XY:

726880

show subpopulations

African (AFR)

AF:

0.0529

AC:

1772

AN:

33474

American (AMR)

AF:

0.167

AC:

7460

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.379

AC:

9893

AN:

26130

East Asian (EAS)

AF:

0.0328

AC:

1303

AN:

39696

South Asian (SAS)

AF:

0.362

AC:

31193

AN:

86240

European-Finnish (FIN)

AF:

0.349

AC:

18566

AN:

53182

Middle Eastern (MID)

AF:

0.358

AC:

2064

AN:

5768

European-Non Finnish (NFE)

AF:

0.353

AC:

392740

AN:

1111486

Other (OTH)

AF:

0.310

AC:

18740

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

17625

35250

52874

70499

88124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12200

24400

36600

48800

61000

<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:

0.245

AC:

37334

AN:

152146

Hom.:

6046

Cov.:

AF XY:

0.242

AC XY:

18022

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0626

AC:

2600

AN:

41518

American (AMR)

AF:

0.198

AC:

3034

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.374

AC:

1298

AN:

3470

East Asian (EAS)

AF:

0.0401

AC:

208

AN:

5184

South Asian (SAS)

AF:

0.351

AC:

1690

AN:

4816

European-Finnish (FIN)

AF:

0.348

AC:

3678

AN:

10576

Middle Eastern (MID)

AF:

0.332

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.354

AC:

24037

AN:

67982

Other (OTH)

AF:

0.251

AC:

528

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1351

2702

4053

5404

6755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

392

784

1176

1568

1960

<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:

0.309

Hom.:

12641

Bravo

AF:

0.221

Asia WGS

AF:

0.156

AC:

541

AN:

3478

EpiCase

AF:

0.343

EpiControl

AF:

0.343

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neuroblastoma, susceptibility to, 3 (5)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.18

(source)

DANN

Benign

0.78

PhyloP100

-1.2

PromoterAI

0.10

Neutral

(source)

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000059

dbscSNV1_RF

Benign

0.012

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over