rs2293563

Positions:

• chr2-29226953-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004304.5(ALK):​c.3036G>A​(p.Thr1012=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.19

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]

ACMG classification

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	UniProt
ALK	NM_004304.5	c.3036G>A	p.Thr1012=	synonymous_variant	18/29	ENST00000389048.8
ALK	XR_001738688.3			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.3036G>A	p.Thr1012=	synonymous_variant	18/29	1	NM_004304.5	P1
ALK	ENST00000618119.4	c.1905G>A	p.Thr635=	synonymous_variant	17/28	5
ALK	ENST00000431873.6	c.204G>A	p.Thr68=	synonymous_variant, NMD_transcript_variant	2/14	5

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26896 AN: 152050 Hom.: 2541 Cov.: 32

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

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.: 35 AF XY: 0.168 AC XY: 122195 AN XY: 727224

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.: 32 AF XY: 0.173 AC XY: 12839 AN XY: 74394

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:8

Revision: criteria provided, multiple submitters, no conflicts

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	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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

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

not provided Benign:1

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. -

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

Other links and lift over

dbSNP: rs2293563; hg19: chr2-29449819; COSMIC: COSV66557745; COSMIC: COSV66557745;