2-29920633-G-C

Variant names:

• chr2-29920633-G-C
• rs4358080
• NM_004304.5:c.27C>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.27C>G​(p.Leu9Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.905 in 1,541,888 control chromosomes in the GnomAD database, including 632,759 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L9L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.89 (59984 hom., cov: 31)
  • Exomes 𝑓: 0.91 (572775 hom.)
• Consequence: ALK NM_004304.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0660
• Publications: 22 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

ENSG00000233862 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 2-29920633-G-C is Benign according to our data. Variant chr2-29920633-G-C is described in ClinVar as Benign. ClinVar VariationId is 259269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.066 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.27C>G	p.Leu9Leu	synonymous_variant	Exon 1 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.954C>G		non_coding_transcript_exon_variant	Exon 1 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.27C>G	p.Leu9Leu	synonymous_variant	Exon 1 of 29	1	NM_004304.5	ENSP00000373700.3
ENSG00000233862	ENST00000669284.1	n.157+34616C>G		intron_variant	Intron 1 of 1
ENSG00000233862	ENST00000769926.1	n.534+5586C>G		intron_variant	Intron 4 of 4

Frequencies

GnomAD3 genomes AF: 0.887 AC: 134873 AN: 152002 Hom.: 59934 Cov.: 31

Gnomad AFR AF: 0.837

Gnomad AMI AF: 0.854

Gnomad AMR AF: 0.920

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.895

Gnomad FIN AF: 0.848

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.884

GnomAD2 exomes AF: 0.907 AC: 128604 AN: 141848 AF XY: 0.904

Gnomad AFR exome AF: 0.832

Gnomad AMR exome AF: 0.938

Gnomad ASJ exome AF: 0.862

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.856

Gnomad NFE exome AF: 0.908

Gnomad OTH exome AF: 0.894

GnomAD4 exome AF: 0.907 AC: 1261113 AN: 1389768 Hom.: 572775 Cov.: 64 AF XY: 0.906 AC XY: 622214 AN XY: 686492

African (AFR) AF: 0.833 AC: 26556 AN: 31878

American (AMR) AF: 0.935 AC: 34146 AN: 36510

Ashkenazi Jewish (ASJ) AF: 0.860 AC: 21701 AN: 25242

East Asian (EAS) AF: 1.00 AC: 36144 AN: 36158

South Asian (SAS) AF: 0.884 AC: 70597 AN: 79856

European-Finnish (FIN) AF: 0.856 AC: 29493 AN: 34464

Middle Eastern (MID) AF: 0.861 AC: 3700 AN: 4298

European-Non Finnish (NFE) AF: 0.910 AC: 986285 AN: 1083312

Other (OTH) AF: 0.904 AC: 52491 AN: 58050

GnomAD4 genome AF: 0.887 AC: 134982 AN: 152120 Hom.: 59984 Cov.: 31 AF XY: 0.887 AC XY: 65915 AN XY: 74352

African (AFR) AF: 0.837 AC: 34769 AN: 41534

American (AMR) AF: 0.920 AC: 14075 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.855 AC: 2965 AN: 3466

East Asian (EAS) AF: 0.999 AC: 5112 AN: 5116

South Asian (SAS) AF: 0.895 AC: 4308 AN: 4816

European-Finnish (FIN) AF: 0.848 AC: 8986 AN: 10598

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.910 AC: 61864 AN: 67974

Other (OTH) AF: 0.886 AC: 1871 AN: 2112

Alfa AF: 0.896 Hom.: 11207

Bravo AF: 0.891

Asia WGS AF: 0.949 AC: 3300 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:5

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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control 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

- -

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not provided Benign:2

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.27C>G variant affects a non-conserved nucleotide, resulting in no amino acid change. 5/5 splice-site tools in Alamut predict no effect on normal splicing. This variant is found in 20199/22570 control chromosomes (9031 homozygotes) at a frequency of 0.894949, which is about 2147877 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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.61
CADD	Benign	8.3
DANN	Benign	0.56
PhyloP100		0.066
Mutation Taster		=100/0	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: rs4358080; hg19: chr2-30143499; COSMIC: COSV66573286;