2-29320797-T-C

Variant names:

• chr2-29320797-T-C
• rs2293564
• NM_004304.5:c.1500A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004304.5(ALK):​c.1500A>G​(p.Gln500Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.894 in 1,613,924 control chromosomes in the GnomAD database, including 651,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (51141 hom., cov: 32)
  • Exomes 𝑓: 0.90 (600712 hom.)
• Consequence: ALK NM_004304.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.140
• Publications: 29 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-29320797-T-C is Benign according to our data. Variant chr2-29320797-T-C is described in ClinVar as Benign. ClinVar VariationId is 259266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.1500A>G	p.Gln500Gln	synonymous_variant	Exon 7 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.2427A>G		non_coding_transcript_exon_variant	Exon 7 of 18
LOC101929386	XR_007086263.1	n.376+824T>C		intron_variant	Intron 2 of 4
LOC101929386	XR_939920.3	n.89-682T>C		intron_variant	Intron 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.1500A>G	p.Gln500Gln	synonymous_variant	Exon 7 of 29	1	NM_004304.5	ENSP00000373700.3

Frequencies

GnomAD3 genomes AF: 0.801 AC: 121799 AN: 152014 Hom.: 51134 Cov.: 32

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.958

Gnomad AMR AF: 0.874

Gnomad ASJ AF: 0.898

Gnomad EAS AF: 0.914

Gnomad SAS AF: 0.868

Gnomad FIN AF: 0.917

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.919

Gnomad OTH AF: 0.829

GnomAD2 exomes AF: 0.878 AC: 220708 AN: 251468 AF XY: 0.884

Gnomad AFR exome AF: 0.504

Gnomad AMR exome AF: 0.885

Gnomad ASJ exome AF: 0.896

Gnomad EAS exome AF: 0.907

Gnomad FIN exome AF: 0.914

Gnomad NFE exome AF: 0.918

Gnomad OTH exome AF: 0.896

GnomAD4 exome AF: 0.904 AC: 1321580 AN: 1461792 Hom.: 600712 Cov.: 57 AF XY: 0.904 AC XY: 657332 AN XY: 727190

African (AFR) AF: 0.492 AC: 16485 AN: 33478

American (AMR) AF: 0.885 AC: 39597 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.897 AC: 23442 AN: 26136

East Asian (EAS) AF: 0.906 AC: 35962 AN: 39700

South Asian (SAS) AF: 0.866 AC: 74717 AN: 86252

European-Finnish (FIN) AF: 0.919 AC: 49068 AN: 53420

Middle Eastern (MID) AF: 0.869 AC: 5000 AN: 5752

European-Non Finnish (NFE) AF: 0.921 AC: 1023908 AN: 1111948

Other (OTH) AF: 0.884 AC: 53401 AN: 60384

GnomAD4 genome AF: 0.801 AC: 121840 AN: 152132 Hom.: 51141 Cov.: 32 AF XY: 0.803 AC XY: 59713 AN XY: 74394

African (AFR) AF: 0.514 AC: 21313 AN: 41430

American (AMR) AF: 0.874 AC: 13380 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.898 AC: 3118 AN: 3472

East Asian (EAS) AF: 0.914 AC: 4717 AN: 5162

South Asian (SAS) AF: 0.870 AC: 4198 AN: 4824

European-Finnish (FIN) AF: 0.917 AC: 9720 AN: 10602

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.919 AC: 62522 AN: 68018

Other (OTH) AF: 0.825 AC: 1744 AN: 2114

Alfa AF: 0.872 Hom.: 45477

Bravo AF: 0.785

Asia WGS AF: 0.842 AC: 2928 AN: 3478

EpiCase AF: 0.917

EpiControl AF: 0.913

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:6

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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. -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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

- -

not specified Benign:3

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Mar 02, 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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 27, 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 c.1500A>G variant affects a non-conserved nucleotide, resulting in no amino acid change. One in-silico tool predicts polymorphism outcome for this variant. This variant is found in 105818/121402 control chromosomes (46888 homozygotes) at a frequency of 0.8716331, which is about 2091919 times of the maximal expected frequency of a pathogenic allele (0.0000004), suggesting this variant to be the ancestral allele; therefore it is classified as Benign. -

Hereditary cancer-predisposing syndrome Benign:1

Dec 08, 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
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.0
DANN	Benign	0.39
PhyloP100		-0.14
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: rs2293564; hg19: chr2-29543663; COSMIC: COSV66566490; COSMIC: COSV66566490;