dbSNP rs10495771: ALK:c.668-58598T>G (chr2-29776295-A-C) – 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.668-58598T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.89 ( 49832 hom., cov: 15)

Consequence

ALK
NM_004304.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.532

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:

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=-0.92).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.978 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5 link	c.668-58598T>G		intron_variant	Intron 1 of 28	ENST00000389048.8	NP_004295.2	Q9UM73B6D4Y2
ALK	XR_001738688.3 link	n.1595-58598T>G		intron_variant	Intron 1 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8 link	c.668-58598T>G		intron_variant	Intron 1 of 28	1	NM_004304.5	ENSP00000373700.3		Q9UM73

Frequencies

GnomAD3 genomes

AF:

0.894

AC:

109303

AN:

122330

Hom.:

49820

Cov.:

show subpopulations

Gnomad AFR

AF:

0.711

Gnomad AMI

AF:

0.970

Gnomad AMR

AF:

0.931

Gnomad ASJ

AF:

0.985

Gnomad EAS

AF:

0.978

Gnomad SAS

AF:

0.909

Gnomad FIN

AF:

0.995

Gnomad MID

AF:

0.942

Gnomad NFE

AF:

0.984

Gnomad OTH

AF:

0.911

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

GnomAD4 genome

AF:

0.893

AC:

109344

AN:

122402

Hom.:

49832

Cov.:

AF XY:

0.890

AC XY:

50512

AN XY:

56754

show subpopulations

African (AFR)

AF:

0.711

AC:

26711

AN:

37558

American (AMR)

AF:

0.932

AC:

9115

AN:

9784

Ashkenazi Jewish (ASJ)

AF:

0.985

AC:

2993

AN:

3040

East Asian (EAS)

AF:

0.977

AC:

3853

AN:

3942

South Asian (SAS)

AF:

0.909

AC:

3023

AN:

3326

European-Finnish (FIN)

AF:

0.995

AC:

3801

AN:

3822

Middle Eastern (MID)

AF:

0.943

AC:

181

AN:

192

European-Non Finnish (NFE)

AF:

0.984

AC:

57446

AN:

58354

Other (OTH)

AF:

0.912

AC:

1437

AN:

1576

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

404

808

1213

1617

2021

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

702

1404

2106

2808

3510

<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:

0.965

Hom.:

79837

Bravo

AF:

0.901

Asia WGS

AF:

0.947

AC:

3262

AN:

3444

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.7

(source)

DANN

Benign

0.76

PhyloP100

-0.53

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