rs1881421

chr2-29193500-G-C

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.4587C>G(p.Asp1529Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 1,613,842 control chromosomes in the GnomAD database, including 137,955 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. D1529N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.48 (18503 hom., cov: 32)
  • Exomes 𝑓: 0.39 (119452 hom.)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:14 O:1
• Conservation: PhyloP100: -0.102

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=1.4798009E-6).
• BP6: Variant 2-29193500-G-C is Benign according to our data. Variant chr2-29193500-G-C is described in ClinVar as [Benign]. Clinvar id is 133476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-29193500-G-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.4587C>G	p.Asp1529Glu	missense_variant	29/29	ENST00000389048.8
ALK	NM_001353765.2	c.1383C>G	p.Asp461Glu	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.4587C>G	p.Asp1529Glu	missense_variant	29/29	1	NM_004304.5	P1

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72103 AN: 151896 Hom.: 18456 Cov.: 32

Gnomad AFR AF: 0.616

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.549

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.735

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.496

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.453

GnomAD3 exomes AF: 0.468 AC: 117649 AN: 251122 Hom.: 30306 AF XY: 0.454 AC XY: 61554 AN XY: 135712

Gnomad AFR exome AF: 0.626

Gnomad AMR exome AF: 0.660

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.746

Gnomad SAS exome AF: 0.458

Gnomad FIN exome AF: 0.490

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.417

GnomAD4 exome AF: 0.392 AC: 573213 AN: 1461828 Hom.: 119452 Cov.: 67 AF XY: 0.391 AC XY: 284364 AN XY: 727214

Gnomad4 AFR exome AF: 0.623

Gnomad4 AMR exome AF: 0.643

Gnomad4 ASJ exome AF: 0.309

Gnomad4 EAS exome AF: 0.726

Gnomad4 SAS exome AF: 0.455

Gnomad4 FIN exome AF: 0.485

Gnomad4 NFE exome AF: 0.356

Gnomad4 OTH exome AF: 0.401

GnomAD4 genome AF: 0.475 AC: 72209 AN: 152014 Hom.: 18503 Cov.: 32 AF XY: 0.485 AC XY: 36007 AN XY: 74314

Gnomad4 AFR AF: 0.616

Gnomad4 AMR AF: 0.550

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.735

Gnomad4 SAS AF: 0.466

Gnomad4 FIN AF: 0.496

Gnomad4 NFE AF: 0.358

Gnomad4 OTH AF: 0.458

Alfa AF: 0.378 Hom.: 8704

Bravo AF: 0.490

TwinsUK AF: 0.341 AC: 1264

ALSPAC AF: 0.367 AC: 1413

ESP6500AA AF: 0.608 AC: 2681

ESP6500EA AF: 0.344 AC: 2957

ExAC AF: 0.460 AC: 55843

Asia WGS AF: 0.613 AC: 2132 AN: 3478

EpiCase AF: 0.350

EpiControl AF: 0.355

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:7

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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	Invitae	Feb 01, 2024	- -
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, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 15, 2016	- -

not specified Benign:5 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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 -

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 c.4587C>G variant affects a non-conserved nucleotide, resulting in amino acid change from Asp to Glu. 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 55828/121360 control chromosomes (14197 homozygotes) at a frequency of 0.4600198, which is about 1104047 times of the maximal expected frequency of a pathogenic allele (0.0000004), 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	0.060
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.041
Dann	Benign	0.59
DEOGEN2	Benign	0.0070	T;T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00049	N
LIST_S2	Benign	0.053	T;T;T
MetaRNN	Benign	0.0000015	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
Polyphen		0.0	.;B;.
Vest4		0.015, 0.0060
MutPred		0.097		.;Loss of catalytic residue at D1529 (P = 0.0319);.;
MPC		0.16
ClinPred		0.0045	T
GERP RS		-3.4
Varity_R		0.026
gMVP		0.061

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

LitVar

Other links and lift over

dbSNP: rs1881421; hg19: chr2-29416366; COSMIC: COSV66569695; COSMIC: COSV66569695;