2-29193500-G-C

Position:

chr2-29193500-G-C

Variant summary

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

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 18503 hom., cov: 32)

Exomes 𝑓: 0.39 ( 119452 hom. )

Consequence

ALK
NM_004304.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:15O:1

Conservation

PhyloP100: -0.102

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:

ALK (HGNC:):

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=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	Protein	UniProt
ALK	NM_004304.5 linkuse as main transcript	c.4587C>G	p.Asp1529Glu	missense_variant	29/29	ENST00000389048.8	NP_004295.2	Q9UM73B6D4Y2
ALK	NM_001353765.2 linkuse as main transcript	c.1383C>G	p.Asp461Glu	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.4587C>G	p.Asp1529Glu	missense_variant	29/29	1	NM_004304.5	ENSP00000373700.3		Q9UM73

Frequencies

GnomAD3 genomes

AF:

0.475

AC:

72103

AN:

151896

Hom.:

18456

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.391

AC XY:

284364

AN XY:

727214

show subpopulations

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.:

AF XY:

0.485

AC XY:

36007

AN XY:

74314

show subpopulations

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:1Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 15, 2016	- -

not specified

Benign:5Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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. -

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 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. -
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

0.060

BayesDel_addAF

Benign

-0.85

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

LIST_S2

Benign

0.053

T;T;T

MetaRNN

Benign

0.0000015

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.69

.;N;.

PrimateAI

Benign

0.35

PROVEAN

Benign

1.2

.;N;.

REVEL

Benign

0.063

Sift

Benign

1.0

.;T;.

Sift4G

Benign

1.0

.;T;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

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

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