2-29193706-T-C

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.4381A>G(p.Ile1461Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,611,610 control chromosomes in the GnomAD database, including 803,064 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1461L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.99 ( 74833 hom., cov: 32)

Exomes 𝑓: 1.0 ( 728231 hom. )

Consequence

ALK
NM_004304.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:17O:1

Conservation

PhyloP100: -0.984

Publications

64 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 links:

CLIP4 (HGNC:26108): (CAP-Gly domain containing linker protein family member 4) Predicted to enable microtubule plus-end binding activity. Predicted to be involved in cytoplasmic microtubule organization. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

CLIP4 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 (MetaRNN=7.2734883E-7).

BP6

Variant 2-29193706-T-C is Benign according to our data. Variant chr2-29193706-T-C is described in ClinVar as Benign. ClinVar VariationId is 133472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5 link	c.4381A>G	p.Ile1461Val	missense_variant	Exon 29 of 29	ENST00000389048.8	NP_004295.2
ALK	NM_001353765.2 link	c.1177A>G	p.Ile393Val	missense_variant	Exon 10 of 10		NP_001340694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8 link	c.4381A>G	p.Ile1461Val	missense_variant	Exon 29 of 29	1	NM_004304.5	ENSP00000373700.3

Frequencies

GnomAD3 genomes

AF:

0.991

AC:

150841

AN:

152166

Hom.:

74774

Cov.:

show subpopulations

Gnomad AFR

AF:

0.969

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.998

Gnomad ASJ

AF:

0.996

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.994

GnomAD2 exomes

AF:

0.998

AC:

249995

AN:

250608

AF XY:

0.998

show subpopulations

Gnomad AFR exome

AF:

0.969

Gnomad AMR exome

AF:

0.999

Gnomad ASJ exome

AF:

0.996

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.999

GnomAD4 exome

AF:

0.999

AC:

1457866

AN:

1459326

Hom.:

728231

Cov.:

AF XY:

0.999

AC XY:

724917

AN XY:

725568

show subpopulations

African (AFR)

AF:

0.967

AC:

32271

AN:

33360

American (AMR)

AF:

0.999

AC:

44517

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.996

AC:

25946

AN:

26046

East Asian (EAS)

AF:

1.00

AC:

39656

AN:

39656

South Asian (SAS)

AF:

1.00

AC:

86192

AN:

86192

European-Finnish (FIN)

AF:

1.00

AC:

53366

AN:

53366

Middle Eastern (MID)

AF:

0.998

AC:

5752

AN:

5764

European-Non Finnish (NFE)

AF:

1.00

AC:

1109984

AN:

1110102

Other (OTH)

AF:

0.998

AC:

60182

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

194

292

389

486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21670

43340

65010

86680

108350

<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:

0.991

AC:

150959

AN:

152284

Hom.:

74833

Cov.:

AF XY:

0.992

AC XY:

73842

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.970

AC:

40297

AN:

41562

American (AMR)

AF:

0.998

AC:

15277

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.996

AC:

3458

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5162

AN:

5162

South Asian (SAS)

AF:

1.00

AC:

4816

AN:

4816

European-Finnish (FIN)

AF:

1.00

AC:

10614

AN:

10614

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68028

AN:

68038

Other (OTH)

AF:

0.994

AC:

2101

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

130

194

259

324

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.996

Hom.:

185042

Bravo

AF:

0.990

TwinsUK

AF:

1.00

AC:

3707

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.972

AC:

4283

ESP6500EA

AF:

1.00

AC:

8597

ExAC

AF:

0.997

AC:

121066

Asia WGS

AF:

1.00

AC:

3476

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3

Benign:9

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 15, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

not specified

Benign:5Other:1

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 10, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Mar 02, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Apr 27, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The c.4381A>G variant affects a non-conserved nucleotide, resulting in amino acid change from Ile to Val. 4/4 in-silico tools predict benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 120930/121274 control chromosomes (60296 homozygotes) at a frequency of 0.9971634, which is about 2393192 times of the maximal expected frequency of a pathogenic allele (0.0000004), suggesting the variant to be the ancestral allele; therefore it is classified as Benign.

Squamous cell lung carcinoma

Pathogenic:1

May 05, 2020

Faculté Pluridciplinaire Nador, Université Mohamed Premier

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing;in vivo

Hereditary cancer-predisposing syndrome

Benign:1

Dec 08, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0090

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.010

T;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0048

LIST_S2

Benign

0.086

T;T;T

MetaRNN

Benign

7.3e-7

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

.;N;.

PhyloP100

-0.98

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.0

.;N;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;T;.

Sift4G

Pathogenic

0.0

.;T;T

Vest4

0.0

ClinPred

0.0021

GERP RS

-0.13

Varity_R

0.017

gMVP

0.075

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over