rs1881420

chr2-29193615-T-Cchr2-29193615-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004304.5(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. 13/19 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 NM_004304.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:12 O:1
• Conservation: PhyloP100: 1.81

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]

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]

ACMG classification

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	UniProt
ALK	NM_004304.5	c.4472A>G	p.Lys1491Arg	missense_variant	29/29	ENST00000389048.8
ALK	NM_001353765.2	c.1268A>G	p.Lys423Arg	missense_variant	10/10

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42416 AN: 152054 Hom.: 7110 Cov.: 33

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

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.: 73 AF XY: 0.262 AC XY: 190851 AN XY: 727240

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.: 33 AF XY: 0.291 AC XY: 21664 AN XY: 74374

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:1 Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5 Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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 -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

- -

not provided Benign:1

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. -

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	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.020	T;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.58	T;T;T
MetaRNN	Benign	0.0000025	T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.42	T
Polyphen		0.0	.;B;.
Vest4		0.035, 0.025
MPC		0.14
ClinPred		0.0063	T
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

Other links and lift over

dbSNP: rs1881420; hg19: chr2-29416481; COSMIC: COSV66555753; COSMIC: COSV66555753;