2-29717663-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004304.5(ALK):c.702T>A(p.Pro234Pro) variant causes a synonymous change. The variant allele was found at a frequency of 0.773 in 1,613,634 control chromosomes in the GnomAD database, including 494,258 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. P234P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.64 ( 35608 hom., cov: 32)

Exomes 𝑓: 0.79 ( 458650 hom. )

Consequence

ALK
NM_004304.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.80

Publications

36 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 2-29717663-A-T is Benign according to our data. Variant chr2-29717663-A-T is described in ClinVar as Benign. ClinVar VariationId is 259274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.808 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.702T>A	p.Pro234Pro	synonymous	Exon 2 of 29	NP_004295.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.702T>A	p.Pro234Pro	synonymous	Exon 2 of 29	ENSP00000373700.3	Q9UM73
	ALK	ENST00000618119.4	TSL:5	c.-430T>A		5_prime_UTR	Exon 1 of 28	ENSP00000482733.1	A0A087WZL3

Frequencies

GnomAD3 genomes

AF:

0.640

AC:

97210

AN:

151990

Hom.:

35610

Cov.:

show subpopulations

Gnomad AFR

AF:

0.251

Gnomad AMI

AF:

0.917

Gnomad AMR

AF:

0.720

Gnomad ASJ

AF:

0.823

Gnomad EAS

AF:

0.764

Gnomad SAS

AF:

0.707

Gnomad FIN

AF:

0.737

Gnomad MID

AF:

0.718

Gnomad NFE

AF:

0.813

Gnomad OTH

AF:

0.707

GnomAD2 exomes

AF:

0.741

AC:

186258

AN:

251412

AF XY:

0.750

show subpopulations

Gnomad AFR exome

AF:

0.235

Gnomad AMR exome

AF:

0.729

Gnomad ASJ exome

AF:

0.820

Gnomad EAS exome

AF:

0.745

Gnomad FIN exome

AF:

0.747

Gnomad NFE exome

AF:

0.814

Gnomad OTH exome

AF:

0.782

GnomAD4 exome

AF:

0.786

AC:

1149377

AN:

1461526

Hom.:

458650

Cov.:

AF XY:

0.786

AC XY:

571704

AN XY:

727086

show subpopulations

African (AFR)

AF:

0.224

AC:

7505

AN:

33478

American (AMR)

AF:

0.730

AC:

32645

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.824

AC:

21521

AN:

26132

East Asian (EAS)

AF:

0.785

AC:

31156

AN:

39692

South Asian (SAS)

AF:

0.711

AC:

61290

AN:

86246

European-Finnish (FIN)

AF:

0.752

AC:

40145

AN:

53412

Middle Eastern (MID)

AF:

0.788

AC:

4543

AN:

5766

European-Non Finnish (NFE)

AF:

0.813

AC:

904177

AN:

1111696

Other (OTH)

AF:

0.768

AC:

46395

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

13189

26378

39567

52756

65945

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20722

41444

62166

82888

103610

<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:

0.639

AC:

97206

AN:

152108

Hom.:

35608

Cov.:

AF XY:

0.640

AC XY:

47592

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.250

AC:

10379

AN:

41500

American (AMR)

AF:

0.720

AC:

11003

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.823

AC:

2856

AN:

3472

East Asian (EAS)

AF:

0.763

AC:

3941

AN:

5164

South Asian (SAS)

AF:

0.706

AC:

3393

AN:

4808

European-Finnish (FIN)

AF:

0.737

AC:

7785

AN:

10570

Middle Eastern (MID)

AF:

0.721

AC:

212

AN:

294

European-Non Finnish (NFE)

AF:

0.813

AC:

55300

AN:

67998

Other (OTH)

AF:

0.710

AC:

1501

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1328

2656

3985

5313

6641

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

750

1500

2250

3000

3750

<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:

0.762

Hom.:

12215

Bravo

AF:

0.622

Asia WGS

AF:

0.734

AC:

2553

AN:

3478

EpiCase

AF:

0.815

EpiControl

AF:

0.824

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neuroblastoma, susceptibility to, 3 (6)

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

-0.56

CADD

Benign

8.0

(source)

DANN

Benign

0.50

PhyloP100

3.8

PromoterAI

-0.0054

Neutral

(source)

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