rs35228363

Variant names:

• chr2-29275101-G-A
• rs35228363
• NM_004304.5:c.2039C>T

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.2039C>T​(p.Thr680Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0232 in 1,614,040 control chromosomes in the GnomAD database, including 542 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T680K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (19 hom., cov: 32)
  • Exomes 𝑓: 0.024 (523 hom.)
• Consequence: ALK NM_004304.5 missense, splice_region
• Scores: Splicing: ADA: 0.9780
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 4.56
• Publications: 30 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070204437).
• BP6: Variant 2-29275101-G-A is Benign according to our data. Variant chr2-29275101-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133462.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 = 0.0157 (2390/152290) while in subpopulation NFE AF = 0.0244 (1663/68018). AF 95% confidence interval is 0.0235. There are 19 homozygotes in GnomAd4. There are 1083 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2390 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004304.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	NM_004304.5	MANE Select	c.2039C>T	p.Thr680Ile	missense splice_region	Exon 11 of 29	NP_004295.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.2039C>T	p.Thr680Ile	missense splice_region	Exon 11 of 29	ENSP00000373700.3
	ALK	ENST00000618119.4	TSL:5	c.908C>T	p.Thr303Ile	missense splice_region	Exon 10 of 28	ENSP00000482733.1

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2390 AN: 152172 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00524

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0244

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0163 AC: 4104 AN: 251472 AF XY: 0.0168

Gnomad AFR exome AF: 0.00412

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.00923

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0204

Gnomad NFE exome AF: 0.0251

Gnomad OTH exome AF: 0.0213

GnomAD4 exome AF: 0.0239 AC: 34991 AN: 1461750 Hom.: 523 Cov.: 32 AF XY: 0.0236 AC XY: 17133 AN XY: 727176

African (AFR) AF: 0.00352 AC: 118 AN: 33478

American (AMR) AF: 0.0116 AC: 519 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00849 AC: 222 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00425 AC: 367 AN: 86252

European-Finnish (FIN) AF: 0.0195 AC: 1040 AN: 53420

Middle Eastern (MID) AF: 0.00581 AC: 33 AN: 5680

European-Non Finnish (NFE) AF: 0.0283 AC: 31430 AN: 1111982

Other (OTH) AF: 0.0209 AC: 1261 AN: 60378

GnomAD4 genome AF: 0.0157 AC: 2390 AN: 152290 Hom.: 19 Cov.: 32 AF XY: 0.0145 AC XY: 1083 AN XY: 74468

African (AFR) AF: 0.00522 AC: 217 AN: 41554

American (AMR) AF: 0.0131 AC: 201 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4824

European-Finnish (FIN) AF: 0.0199 AC: 211 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0244 AC: 1663 AN: 68018

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0224 Hom.: 158

Bravo AF: 0.0156

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0319 AC: 123

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0291 AC: 250

ExAC AF: 0.0159 AC: 1925

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.0261

EpiControl AF: 0.0261

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:6

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 22, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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

Jan 13, 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.

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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Aug 24, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The ALK c.2039C>T (p.Thr680Ile) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1947/122770 control chromosomes (22 homozygotes) at a frequency of 0.0158589, which is approximately 38061 times the estimated maximal expected allele frequency of a pathogenic ALK variant (0.0000004) based on the disease prevalence of neuroblastoma (susceptibility phenotype), suggesting this variant is likely a benign polymorphism. This variant has been reported in patients with breast cancer and prostate cancer as a germline variant and in patients with hemangioblastoma as a somatic variant; however without strong evidence for pathogenicity (Haiman_2013, Harismendy _2013, Shankar_2014). In a large case-control study that included patients with prostate cancer from multiple ethnicities (African American, Native Hawaiian, Japanese American, Latino and European American), it did not confer an increased risk for prostate cancer in the overall population (Haiman_2013). However, in African American subpopulation, it conferred an elevated risk (odd ratio: 3.104; p-value 0.00025), suggesting that it may confer an ethnicity-specific risk. More reproducible case-control studies are required to confirm this risk association. In ClinVar, one clinical lab has classified it as uncertain significance. Taken together, this variant is currently classified as likely benign.

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ALK: BS1, BS2

not specified Benign:2 Other:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Sep 20, 2016

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.022
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.27
Sift	Benign	0.11	T
Sift4G	Benign	0.50	T
Polyphen		0.078	B
Vest4		0.40
MPC		0.39
ClinPred		0.014	T
GERP RS		5.2
Varity_R		0.10
gMVP		0.44
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.55
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: rs35228363; hg19: chr2-29497967;