rs2293563

Positions:

chr2-29226953-C-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.3036G>A(p.Thr1012Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,614,020 control chromosomes in the GnomAD database, including 23,683 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2540 hom., cov: 32)

Exomes 𝑓: 0.17 ( 21143 hom. )

Consequence

ALK
NM_004304.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -3.19

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:

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=-0.77).

BP6

Variant 2-29226953-C-T is Benign according to our data. Variant chr2-29226953-C-T is described in ClinVar as [Benign]. Clinvar id is 259270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-29226953-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.19 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.206 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.3036G>A	p.Thr1012Thr	synonymous_variant	18/29	ENST00000389048.8	NP_004295.2	Q9UM73B6D4Y2
ALK	XR_001738688.3 linkuse as main transcript	n.*34G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ALK	ENST00000389048.8 linkuse as main transcript	c.3036G>A	p.Thr1012Thr	synonymous_variant	18/29	1	NM_004304.5	ENSP00000373700.3	Q9UM73
ALK	ENST00000618119.4 linkuse as main transcript	c.1905G>A	p.Thr635Thr	synonymous_variant	17/28	5		ENSP00000482733.1	A0A087WZL3
ALK	ENST00000431873.6 linkuse as main transcript	n.201G>A		non_coding_transcript_exon_variant	2/14	5		ENSP00000414027.3	E7EPW7

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26896

AN:

152050

Hom.:

2541

Cov.:

show subpopulations

Gnomad AFR

AF:

0.210

Gnomad AMI

AF:

0.154

Gnomad AMR

AF:

0.170

Gnomad ASJ

AF:

0.238

Gnomad EAS

AF:

0.122

Gnomad SAS

AF:

0.140

Gnomad FIN

AF:

0.112

Gnomad MID

AF:

0.245

Gnomad NFE

AF:

0.171

Gnomad OTH

AF:

0.205

GnomAD3 exomes

AF:

0.156

AC:

39273

AN:

251414

Hom.:

3252

AF XY:

0.158

AC XY:

21531

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.208

Gnomad AMR exome

AF:

0.107

Gnomad ASJ exome

AF:

0.244

Gnomad EAS exome

AF:

0.121

Gnomad SAS exome

AF:

0.144

Gnomad FIN exome

AF:

0.109

Gnomad NFE exome

AF:

0.172

Gnomad OTH exome

AF:

0.192

GnomAD4 exome

AF:

0.167

AC:

244783

AN:

1461852

Hom.:

21143

Cov.:

AF XY:

0.168

AC XY:

122195

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.210

Gnomad4 AMR exome

AF:

0.115

Gnomad4 ASJ exome

AF:

0.243

Gnomad4 EAS exome

AF:

0.125

Gnomad4 SAS exome

AF:

0.144

Gnomad4 FIN exome

AF:

0.113

Gnomad4 NFE exome

AF:

0.171

Gnomad4 OTH exome

AF:

0.183

GnomAD4 genome

AF:

0.177

AC:

26894

AN:

152168

Hom.:

2540

Cov.:

AF XY:

0.173

AC XY:

12839

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.210

Gnomad4 AMR

AF:

0.169

Gnomad4 ASJ

AF:

0.238

Gnomad4 EAS

AF:

0.122

Gnomad4 SAS

AF:

0.139

Gnomad4 FIN

AF:

0.112

Gnomad4 NFE

AF:

0.171

Gnomad4 OTH

AF:

0.203

Alfa

AF:

0.180

Hom.:

4257

Bravo

AF:

0.184

Asia WGS

AF:

0.158

AC:

550

AN:

3478

EpiCase

AF:

0.185

EpiControl

AF:

0.184

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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 12, 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. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 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. -

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.3036G>A in ALK gene is a synonymous change that involves a non-conserved nucleotide. 3/5 splice-site tools in Alamut predict that this variant disrupts a cryptic splice donor site meanwhile creating a cryptic splice acceptor site as predicted by 2/5 tools; however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 16%. The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.0004%, suggesting that it is a benign polymorphism. The variant of interest has not been reported by reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was 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 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

-0.77

CADD

Benign

0.22

DANN

Benign

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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