rs138668699

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004304.5(ALK):c.2676C>T(p.Ala892Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,601,550 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A892A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0011 ( 9 hom. )

Consequence

ALK
NM_004304.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0200

Publications

3 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 2-29229023-G-A is Benign according to our data. Variant chr2-29229023-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.02 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00159 (227/142578) while in subpopulation EAS AF = 0.0044 (21/4774). AF 95% confidence interval is 0.00295. There are 0 homozygotes in GnomAd4. There are 137 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 227 AD gene.

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.2676C>T	p.Ala892Ala	synonymous	Exon 16 of 29	NP_004295.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.2676C>T	p.Ala892Ala	synonymous	Exon 16 of 29	ENSP00000373700.3
	ALK	ENST00000618119.4	TSL:5	c.1545C>T	p.Ala515Ala	synonymous	Exon 15 of 28	ENSP00000482733.1

Frequencies

GnomAD3 genomes

AF:

0.00159

AC:

227

AN:

142506

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000316

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000310

Gnomad ASJ

AF:

0.00725

Gnomad EAS

AF:

0.00439

Gnomad SAS

AF:

0.000221

Gnomad FIN

AF:

0.0139

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000553

Gnomad OTH

AF:

0.00254

GnomAD2 exomes

AF:

0.00220

AC:

554

AN:

251330

AF XY:

0.00198

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00923

Gnomad EAS exome

AF:

0.00256

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.000801

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00112

AC:

1639

AN:

1458972

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

784

AN XY:

725720

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33410

American (AMR)

AF:

0.000269

AC:

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.00794

AC:

207

AN:

26056

East Asian (EAS)

AF:

0.00578

AC:

229

AN:

39586

South Asian (SAS)

AF:

0.000383

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.0123

AC:

652

AN:

53178

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.000361

AC:

401

AN:

1109962

Other (OTH)

AF:

0.00156

AC:

AN:

60184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

196

293

391

489

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00159

AC:

227

AN:

142578

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

137

AN XY:

68502

show subpopulations

African (AFR)

AF:

0.000315

AC:

AN:

38104

American (AMR)

AF:

0.000310

AC:

AN:

12914

Ashkenazi Jewish (ASJ)

AF:

0.00725

AC:

AN:

3446

East Asian (EAS)

AF:

0.00440

AC:

AN:

4774

South Asian (SAS)

AF:

0.000222

AC:

AN:

4510

European-Finnish (FIN)

AF:

0.0139

AC:

122

AN:

8760

Middle Eastern (MID)

AF:

0.00

AC:

AN:

256

European-Non Finnish (NFE)

AF:

0.000553

AC:

AN:

66920

Other (OTH)

AF:

0.00252

AC:

AN:

1986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.00114

Hom.:

Bravo

AF:

0.000593

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Neuroblastoma, susceptibility to, 3 (2)

ALK-related disorder (1)

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

8.9

(source)

DANN

Benign

0.70

PhyloP100

0.020

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over