chr2-29920633-G-C

Position:

chr2-29920633-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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 (★★).

Frequency

Genomes: 𝑓 0.89 ( 59984 hom., cov: 31)

Exomes 𝑓: 0.91 ( 572775 hom. )

Consequence

ALK
NM_004304.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.0660

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 259269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-29920633-G-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
ALK	NM_004304.5 linkuse as main transcript	c.27C>G	p.Leu9Leu	synonymous_variant	1/29	ENST00000389048.8	NP_004295.2	Q9UM73B6D4Y2
ALK	XR_001738688.3 linkuse as main transcript	n.954C>G		non_coding_transcript_exon_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8 linkuse as main transcript	c.27C>G	p.Leu9Leu	synonymous_variant	1/29	1	NM_004304.5	ENSP00000373700.3		Q9UM73
ENSG00000288553	ENST00000669284.1 linkuse as main transcript	n.157+34616C>G		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.887

AC:

134873

AN:

152002

Hom.:

59934

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.907

AC:

128604

AN:

141848

Hom.:

58443

AF XY:

0.904

AC XY:

70342

AN XY:

77820

show subpopulations

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 SAS exome

AF:

0.880

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.:

AF XY:

0.906

AC XY:

622214

AN XY:

686492

show subpopulations

Gnomad4 AFR exome

AF:

0.833

Gnomad4 AMR exome

AF:

0.935

Gnomad4 ASJ exome

AF:

0.860

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.884

Gnomad4 FIN exome

AF:

0.856

Gnomad4 NFE exome

AF:

0.910

Gnomad4 OTH exome

AF:

0.904

GnomAD4 genome

AF:

0.887

AC:

134982

AN:

152120

Hom.:

59984

Cov.:

AF XY:

0.887

AC XY:

65915

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.837

Gnomad4 AMR

AF:

0.920

Gnomad4 ASJ

AF:

0.855

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.895

Gnomad4 FIN

AF:

0.848

Gnomad4 NFE

AF:

0.910

Gnomad4 OTH

AF:

0.886

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

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 -

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.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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 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

BayesDel_noAF

Benign

-0.61

CADD

Benign

8.3

DANN

Benign

0.56

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