chr2-29320870-A-G

Variant names:

• chr2-29320870-A-G
• rs35093491
• NM_004304.5:c.1427T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004304.5(ALK):​c.1427T>C​(p.Val476Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0352 in 1,614,174 control chromosomes in the GnomAD database, including 1,139 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V476M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.026 (70 hom., cov: 33)
  • Exomes 𝑓: 0.036 (1069 hom.)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 0.901
• Publications: 27 publications found

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 Gene-Disease associations (from GenCC):

• neuroblastoma, susceptibility to, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000286963 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036117435).
• BP6: Variant 2-29320870-A-G is Benign according to our data. Variant chr2-29320870-A-G is described in ClinVar as Benign. ClinVar VariationId is 133485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0256 (3901/152318) while in subpopulation NFE AF = 0.0372 (2529/68028). AF 95% confidence interval is 0.036. There are 70 homozygotes in GnomAd4. There are 1854 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3901 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.1427T>C	p.Val476Ala	missense_variant	Exon 7 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.2354T>C		non_coding_transcript_exon_variant	Exon 7 of 18
LOC101929386	XR_007086263.1	n.376+897A>G		intron_variant	Intron 2 of 4
LOC101929386	XR_939920.3	n.89-609A>G		intron_variant	Intron 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.1427T>C	p.Val476Ala	missense_variant	Exon 7 of 29	1	NM_004304.5	ENSP00000373700.3

Frequencies

GnomAD3 genomes AF: 0.0256 AC: 3903 AN: 152200 Hom.: 70 Cov.: 33

Gnomad AFR AF: 0.00721

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.0253

Gnomad ASJ AF: 0.0491

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0372

Gnomad OTH AF: 0.0368

GnomAD2 exomes AF: 0.0285 AC: 7167 AN: 251242 AF XY: 0.0300

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0528

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0245

Gnomad NFE exome AF: 0.0385

Gnomad OTH exome AF: 0.0326

GnomAD4 exome AF: 0.0362 AC: 52961 AN: 1461856 Hom.: 1069 Cov.: 36 AF XY: 0.0361 AC XY: 26218 AN XY: 727230

African (AFR) AF: 0.00618 AC: 207 AN: 33480

American (AMR) AF: 0.0189 AC: 847 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0494 AC: 1291 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.0248 AC: 2135 AN: 86258

European-Finnish (FIN) AF: 0.0259 AC: 1384 AN: 53416

Middle Eastern (MID) AF: 0.0187 AC: 108 AN: 5768

European-Non Finnish (NFE) AF: 0.0404 AC: 44909 AN: 1111978

Other (OTH) AF: 0.0343 AC: 2073 AN: 60396

GnomAD4 genome AF: 0.0256 AC: 3901 AN: 152318 Hom.: 70 Cov.: 33 AF XY: 0.0249 AC XY: 1854 AN XY: 74486

African (AFR) AF: 0.00719 AC: 299 AN: 41574

American (AMR) AF: 0.0252 AC: 386 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0491 AC: 170 AN: 3464

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5184

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4820

European-Finnish (FIN) AF: 0.0245 AC: 260 AN: 10624

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0372 AC: 2529 AN: 68028

Other (OTH) AF: 0.0364 AC: 77 AN: 2114

Alfa AF: 0.0343 Hom.: 334

Bravo AF: 0.0257

TwinsUK AF: 0.0450 AC: 167

ALSPAC AF: 0.0454 AC: 175

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.0379 AC: 326

ExAC AF: 0.0293 AC: 3560

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0360

EpiControl AF: 0.0365

ClinVar

Significance: Benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:6

Jan 15, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Nov 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

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. -

not provided Benign:3

Aug 24, 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 ALK c.1427T>C (p.Val476Ala) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 3594/122674 control chromosomes (67 homozygotes) at a frequency of 0.0292972, which is approximately 70313 times the estimated maximal expected allele frequency of a pathogenic ALK variant (0.0000004), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as benign. -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ALK: BP4, BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2017

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. -

Hereditary cancer-predisposing syndrome Benign:1

Dec 14, 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	0.050
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.0
DANN	Benign	0.63
DEOGEN2	Benign	0.080	T;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.26	T;T
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	-0.69	N;.
PhyloP100		0.90
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.34	N;.
REVEL	Benign	0.038
Sift	Benign	0.54	T;.
Sift4G	Benign	0.55	T;T
Polyphen		0.0	B;.
Vest4		0.056
MPC		0.20
ClinPred		0.0029	T
GERP RS		3.0
Varity_R		0.027
gMVP		0.16
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35093491; hg19: chr2-29543736; COSMIC: COSV66568530; COSMIC: COSV66568530;