dbSNP rs1406233: ALK:c.1817+5245G>A (chr2-29291643-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004304.5(ALK):c.1817+5245G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 152,258 control chromosomes in the GnomAD database, including 799 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.10 ( 799 hom., cov: 32)

Consequence

ALK
NM_004304.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.375

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5 link	c.1817+5245G>A		intron_variant	Intron 9 of 28	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3 link	n.2744+5245G>A		intron_variant	Intron 9 of 17

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
ALK	ENST00000389048.8 link	c.1817+5245G>A	intron_variant	Intron 9 of 28	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4 link	c.686+5245G>A	intron_variant	Intron 8 of 27	5		ENSP00000482733.1
ALK	ENST00000498037.1 link	n.373-4809G>A	intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes

AF:

0.100

AC:

15269

AN:

152140

Hom.:

800

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0859

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.0870

Gnomad ASJ

AF:

0.0775

Gnomad EAS

AF:

0.00192

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.0991

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.120

Gnomad OTH

AF:

0.0999

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.100

AC:

15275

AN:

152258

Hom.:

799

Cov.:

AF XY:

0.0990

AC XY:

7373

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0858

AC:

3565

AN:

41542

American (AMR)

AF:

0.0869

AC:

1329

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0775

AC:

269

AN:

3472

East Asian (EAS)

AF:

0.00193

AC:

AN:

5186

South Asian (SAS)

AF:

0.105

AC:

506

AN:

4820

European-Finnish (FIN)

AF:

0.0991

AC:

1051

AN:

10604

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.120

AC:

8190

AN:

68018

Other (OTH)

AF:

0.100

AC:

212

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

708

1416

2125

2833

3541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<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:

0.101

Hom.:

137

Bravo

AF:

0.0968

Asia WGS

AF:

0.0690

AC:

239

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.9

(source)

DANN

Benign

0.82

PhyloP100

-0.38

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over