Genetic Variant ALK:c.2041+10690G>A (chr2-29264409-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.2041+10690G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.599 in 152,158 control chromosomes in the GnomAD database, including 29,284 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 0.60 ( 29284 hom., cov: 34)

Consequence

ALK
NM_004304.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.446

Publications

2 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:

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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=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5 link	c.2041+10690G>A		intron_variant	Intron 11 of 28	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3 link	n.2968+10690G>A		intron_variant	Intron 11 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8 link	c.2041+10690G>A		intron_variant	Intron 11 of 28	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4 link	c.910+10690G>A		intron_variant	Intron 10 of 27	5		ENSP00000482733.1

Frequencies

GnomAD3 genomes

AF:

0.599

AC:

91079

AN:

152040

Hom.:

29273

Cov.:

show subpopulations

Gnomad AFR

AF:

0.348

Gnomad AMI

AF:

0.747

Gnomad AMR

AF:

0.673

Gnomad ASJ

AF:

0.604

Gnomad EAS

AF:

0.757

Gnomad SAS

AF:

0.686

Gnomad FIN

AF:

0.742

Gnomad MID

AF:

0.557

Gnomad NFE

AF:

0.693

Gnomad OTH

AF:

0.589

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

GnomAD4 genome

AF:

0.599

AC:

91120

AN:

152158

Hom.:

29284

Cov.:

AF XY:

0.605

AC XY:

44979

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.347

AC:

14400

AN:

41496

American (AMR)

AF:

0.674

AC:

10308

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.604

AC:

2096

AN:

3470

East Asian (EAS)

AF:

0.756

AC:

3914

AN:

5174

South Asian (SAS)

AF:

0.686

AC:

3310

AN:

4822

European-Finnish (FIN)

AF:

0.742

AC:

7858

AN:

10596

Middle Eastern (MID)

AF:

0.588

AC:

173

AN:

294

European-Non Finnish (NFE)

AF:

0.693

AC:

47130

AN:

67990

Other (OTH)

AF:

0.592

AC:

1250

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1731

3462

5193

6924

8655

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

758

1516

2274

3032

3790

<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:

0.660

Hom.:

12838

Bravo

AF:

0.582

Asia WGS

AF:

0.714

AC:

2482

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.1

(source)

DANN

Benign

0.80

PhyloP100

-0.45

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