rs1881420

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000389048.8(ALK):c.4472A>G(p.Lys1491Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,614,050 control chromosomes in the GnomAD database, including 66,530 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1491Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.28 ( 7126 hom., cov: 33)

Exomes 𝑓: 0.26 ( 59404 hom. )

Consequence

ALK
ENST00000389048.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:13O:1

Conservation

PhyloP100: 1.81

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.522982E-6).

BP6

Variant 2-29193615-T-C is Benign according to our data. Variant chr2-29193615-T-C is described in ClinVar as [Benign]. Clinvar id is 133474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-29193615-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALK	NM_004304.5 linkuse as main transcript	c.4472A>G	p.Lys1491Arg	missense_variant	29/29	ENST00000389048.8	NP_004295.2
ALK	NM_001353765.2 linkuse as main transcript	c.1268A>G	p.Lys423Arg	missense_variant	10/10		NP_001340694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8 linkuse as main transcript	c.4472A>G	p.Lys1491Arg	missense_variant	29/29	1	NM_004304.5	ENSP00000373700	P1

Frequencies

GnomAD3 genomes

AF:

0.279

AC:

42416

AN:

152054

Hom.:

7110

Cov.:

show subpopulations

Gnomad AFR

AF:

0.248

Gnomad AMI

AF:

0.418

Gnomad AMR

AF:

0.425

Gnomad ASJ

AF:

0.177

Gnomad EAS

AF:

0.735

Gnomad SAS

AF:

0.438

Gnomad FIN

AF:

0.306

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.219

Gnomad OTH

AF:

0.273

GnomAD3 exomes

AF:

0.344

AC:

86397

AN:

251410

Hom.:

19009

AF XY:

0.334

AC XY:

45397

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.249

Gnomad AMR exome

AF:

0.588

Gnomad ASJ exome

AF:

0.167

Gnomad EAS exome

AF:

0.747

Gnomad SAS exome

AF:

0.423

Gnomad FIN exome

AF:

0.304

Gnomad NFE exome

AF:

0.223

Gnomad OTH exome

AF:

0.282

GnomAD4 exome

AF:

0.260

AC:

380632

AN:

1461878

Hom.:

59404

Cov.:

AF XY:

0.262

AC XY:

190851

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.247

Gnomad4 AMR exome

AF:

0.563

Gnomad4 ASJ exome

AF:

0.173

Gnomad4 EAS exome

AF:

0.727

Gnomad4 SAS exome

AF:

0.419

Gnomad4 FIN exome

AF:

0.302

Gnomad4 NFE exome

AF:

0.220

Gnomad4 OTH exome

AF:

0.268

GnomAD4 genome

AF:

0.279

AC:

42458

AN:

152172

Hom.:

7126

Cov.:

AF XY:

0.291

AC XY:

21664

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.247

Gnomad4 AMR

AF:

0.425

Gnomad4 ASJ

AF:

0.177

Gnomad4 EAS

AF:

0.736

Gnomad4 SAS

AF:

0.438

Gnomad4 FIN

AF:

0.306

Gnomad4 NFE

AF:

0.219

Gnomad4 OTH

AF:

0.280

Alfa

AF:

0.242

Hom.:

11741

Bravo

AF:

0.291

TwinsUK

AF:

0.200

AC:

742

ALSPAC

AF:

0.223

AC:

861

ESP6500AA

AF:

0.242

AC:

1068

ESP6500EA

AF:

0.214

AC:

1837

ExAC

AF:

0.332

AC:

40280

Asia WGS

AF:

0.578

AC:

2009

AN:

3478

EpiCase

AF:

0.217

EpiControl

AF:

0.220

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Neuroblastoma, susceptibility to, 3

Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2016	Variant summary: The ALK c.4472A>G variant affects a conserved nucleotide, resulting in amino acid change from Lys to Arg. 5/5 in-silico tools predict benign outcome for this variant. This variant was found in 40280/121392 control chromosomes (8650 homozygotes) at a frequency of 0.3318176, which is about 796362 times the maximal expected frequency of a pathogenic ALK allele (0.0000004), highly suggesting this variant is benign. Taken together, this variant was classified as benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Squamous cell lung carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing;in vivo

Faculté Pluridciplinaire Nador, Université Mohamed Premier

May 05, 2020

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2016

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

0.070

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.020

T;T;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.58

T;T;T

MetaRNN

Benign

0.0000025

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.5

.;L;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.42

.;N;.

REVEL

Benign

0.088

Sift

Benign

0.41

.;T;.

Sift4G

Benign

0.26

.;T;T

Polyphen

0.0

.;B;.

Vest4

0.035, 0.025

MPC

0.14

ClinPred

0.0063

GERP RS

1.9

Varity_R

0.036

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over