chr2-29222592-G-T

Position:

chr2-29222592-G-T

Variant summary

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

The NM_004304.5(ALK):c.3375C>A(p.Gly1125=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,612,654 control chromosomes in the GnomAD database, including 63,150 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. G1125G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.28 ( 7079 hom., cov: 31)

Exomes 𝑓: 0.25 ( 56071 hom. )

Consequence

ALK
NM_004304.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.78

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 2-29222592-G-T is Benign according to our data. Variant chr2-29222592-G-T is described in ClinVar as [Benign]. Clinvar id is 335694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-29222592-G-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.78 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5 linkuse as main transcript	c.3375C>A	p.Gly1125=	synonymous_variant	21/29	ENST00000389048.8
ALK	NM_001353765.2 linkuse as main transcript	c.171C>A	p.Gly57=	synonymous_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8 linkuse as main transcript	c.3375C>A	p.Gly1125=	synonymous_variant	21/29	1	NM_004304.5	P1

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

42199

AN:

151786

Hom.:

7062

Cov.:

show subpopulations

Gnomad AFR

AF:

0.258

Gnomad AMI

AF:

0.397

Gnomad AMR

AF:

0.427

Gnomad ASJ

AF:

0.171

Gnomad EAS

AF:

0.728

Gnomad SAS

AF:

0.415

Gnomad FIN

AF:

0.321

Gnomad MID

AF:

0.143

Gnomad NFE

AF:

0.211

Gnomad OTH

AF:

0.271

GnomAD3 exomes

AF:

0.337

AC:

84377

AN:

250420

Hom.:

18404

AF XY:

0.325

AC XY:

44042

AN XY:

135392

show subpopulations

Gnomad AFR exome

AF:

0.259

Gnomad AMR exome

AF:

0.596

Gnomad ASJ exome

AF:

0.161

Gnomad EAS exome

AF:

0.737

Gnomad SAS exome

AF:

0.391

Gnomad FIN exome

AF:

0.315

Gnomad NFE exome

AF:

0.213

Gnomad OTH exome

AF:

0.273

GnomAD4 exome

AF:

0.251

AC:

366774

AN:

1460750

Hom.:

56071

Cov.:

AF XY:

0.252

AC XY:

183450

AN XY:

726740

show subpopulations

Gnomad4 AFR exome

AF:

0.254

Gnomad4 AMR exome

AF:

0.572

Gnomad4 ASJ exome

AF:

0.165

Gnomad4 EAS exome

AF:

0.718

Gnomad4 SAS exome

AF:

0.389

Gnomad4 FIN exome

AF:

0.311

Gnomad4 NFE exome

AF:

0.210

Gnomad4 OTH exome

AF:

0.261

GnomAD4 genome

AF:

0.278

AC:

42247

AN:

151904

Hom.:

7079

Cov.:

AF XY:

0.291

AC XY:

21636

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.258

Gnomad4 AMR

AF:

0.428

Gnomad4 ASJ

AF:

0.171

Gnomad4 EAS

AF:

0.729

Gnomad4 SAS

AF:

0.413

Gnomad4 FIN

AF:

0.321

Gnomad4 NFE

AF:

0.211

Gnomad4 OTH

AF:

0.277

Alfa

AF:

0.219

Hom.:

6742

Bravo

AF:

0.290

Asia WGS

AF:

0.563

AC:

1956

AN:

3478

EpiCase

AF:

0.209

EpiControl

AF:

0.211

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

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 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	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.3375C>A variant involves the alteration of a non-conserved nucleotide resulting in a synonymous change. 4/4 in silico tools via Alamut predict no significant effect on splicing. The variant was observed in the large, broad control population, ExAC with an allele frequency of 32.7% which includes 8232 homozygous occurrences, strong evidence that this is a benign polymorphism. Due to the synonymous nature of this variant and the high allele frequency in the general population, this variant has been classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Squamous cell lung carcinoma

Benign:1

Likely benign, no assertion criteria provided

clinical testing;in vivo

Faculté Pluridciplinaire Nador, Université Mohamed Premier

May 05, 2020

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 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

-0.71

CADD

Benign

0.34

DANN

Benign

0.57

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