rs4358080

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.27C>G(p.Leu9Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.905 in 1,541,888 control chromosomes in the GnomAD database, including 632,759 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. L9L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.89 ( 59984 hom., cov: 31)

Exomes 𝑓: 0.91 ( 572775 hom. )

Consequence

ALK
NM_004304.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0660

Publications

22 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:

ENSG00000233862 (HGNC:):

ENSG00000233862 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=-0.61).

BP6

Variant 2-29920633-G-C is Benign according to our data. Variant chr2-29920633-G-C is described in ClinVar as Benign. ClinVar VariationId is 259269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.066 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.27C>G	p.Leu9Leu	synonymous	Exon 1 of 29	NP_004295.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALK	ENST00000389048.8	TSL:1 MANE Select	c.27C>G	p.Leu9Leu	synonymous	Exon 1 of 29	ENSP00000373700.3	Q9UM73
ENSG00000233862	ENST00000669284.1		n.157+34616C>G		intron	N/A
ENSG00000233862	ENST00000769926.1		n.534+5586C>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.887

AC:

134873

AN:

152002

Hom.:

59934

Cov.:

show subpopulations

Gnomad AFR

AF:

0.837

Gnomad AMI

AF:

0.854

Gnomad AMR

AF:

0.920

Gnomad ASJ

AF:

0.855

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.895

Gnomad FIN

AF:

0.848

Gnomad MID

AF:

0.858

Gnomad NFE

AF:

0.910

Gnomad OTH

AF:

0.884

GnomAD2 exomes

AF:

0.907

AC:

128604

AN:

141848

AF XY:

0.904

show subpopulations

Gnomad AFR exome

AF:

0.832

Gnomad AMR exome

AF:

0.938

Gnomad ASJ exome

AF:

0.862

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.856

Gnomad NFE exome

AF:

0.908

Gnomad OTH exome

AF:

0.894

GnomAD4 exome

AF:

0.907

AC:

1261113

AN:

1389768

Hom.:

572775

Cov.:

AF XY:

0.906

AC XY:

622214

AN XY:

686492

show subpopulations

African (AFR)

AF:

0.833

AC:

26556

AN:

31878

American (AMR)

AF:

0.935

AC:

34146

AN:

36510

Ashkenazi Jewish (ASJ)

AF:

0.860

AC:

21701

AN:

25242

East Asian (EAS)

AF:

1.00

AC:

36144

AN:

36158

South Asian (SAS)

AF:

0.884

AC:

70597

AN:

79856

European-Finnish (FIN)

AF:

0.856

AC:

29493

AN:

34464

Middle Eastern (MID)

AF:

0.861

AC:

3700

AN:

4298

European-Non Finnish (NFE)

AF:

0.910

AC:

986285

AN:

1083312

Other (OTH)

AF:

0.904

AC:

52491

AN:

58050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

6943

13886

20828

27771

34714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21144

42288

63432

84576

105720

<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:

0.887

AC:

134982

AN:

152120

Hom.:

59984

Cov.:

AF XY:

0.887

AC XY:

65915

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.837

AC:

34769

AN:

41534

American (AMR)

AF:

0.920

AC:

14075

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.855

AC:

2965

AN:

3466

East Asian (EAS)

AF:

0.999

AC:

5112

AN:

5116

South Asian (SAS)

AF:

0.895

AC:

4308

AN:

4816

European-Finnish (FIN)

AF:

0.848

AC:

8986

AN:

10598

Middle Eastern (MID)

AF:

0.861

AC:

253

AN:

294

European-Non Finnish (NFE)

AF:

0.910

AC:

61864

AN:

67974

Other (OTH)

AF:

0.886

AC:

1871

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

768

1537

2305

3074

3842

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

902

1804

2706

3608

4510

<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:

0.896

Hom.:

11207

Bravo

AF:

0.891

Asia WGS

AF:

0.949

AC:

3300

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neuroblastoma, susceptibility to, 3 (5)

not specified (3)

not provided (2)

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

8.3

(source)

DANN

Benign

0.56

PhyloP100

0.066

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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