2-29226953-C-T

Variant names:

• chr2-29226953-C-T
• rs2293563
• NM_004304.5:c.3036G>A

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.19
• Publications: 23 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 259270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.3036G>A	p.Thr1012Thr	synonymous_variant	Exon 18 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.*34G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.3036G>A	p.Thr1012Thr	synonymous_variant	Exon 18 of 29	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.1905G>A	p.Thr635Thr	synonymous_variant	Exon 17 of 28	5		ENSP00000482733.1
ALK	ENST00000431873.6	n.201G>A		non_coding_transcript_exon_variant	Exon 2 of 14	5		ENSP00000414027.3

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

GnomAD2 exomes AF: 0.156 AC: 39273 AN: 251414 AF XY: 0.158

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 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

African (AFR) AF: 0.210 AC: 7022 AN: 33478

American (AMR) AF: 0.115 AC: 5161 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 6355 AN: 26136

East Asian (EAS) AF: 0.125 AC: 4948 AN: 39700

South Asian (SAS) AF: 0.144 AC: 12396 AN: 86256

European-Finnish (FIN) AF: 0.113 AC: 6042 AN: 53414

Middle Eastern (MID) AF: 0.230 AC: 1323 AN: 5762

European-Non Finnish (NFE) AF: 0.171 AC: 190510 AN: 1111986

Other (OTH) AF: 0.183 AC: 11026 AN: 60396

GnomAD4 genome AF: 0.177 AC: 26894 AN: 152168 Hom.: 2540 Cov.: 32 AF XY: 0.173 AC XY: 12839 AN XY: 74394

African (AFR) AF: 0.210 AC: 8707 AN: 41494

American (AMR) AF: 0.169 AC: 2592 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 826 AN: 3472

East Asian (EAS) AF: 0.122 AC: 630 AN: 5174

South Asian (SAS) AF: 0.139 AC: 669 AN: 4816

European-Finnish (FIN) AF: 0.112 AC: 1183 AN: 10604

Middle Eastern (MID) AF: 0.247 AC: 72 AN: 292

European-Non Finnish (NFE) AF: 0.171 AC: 11646 AN: 67996

Other (OTH) AF: 0.203 AC: 429 AN: 2112

Alfa AF: 0.180 Hom.: 4891

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

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:4

Jan 12, 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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

May 06, 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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary cancer-predisposing syndrome Benign:1

Dec 12, 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	-0.77
CADD	Benign	0.22
DANN	Benign	0.45
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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