2-29717663-A-T

Variant names:

• chr2-29717663-A-T
• rs2246745
• NM_004304.5:c.702T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004304.5(ALK):​c.702T>A​(p.Pro234Pro) variant causes a synonymous change. The variant allele was found at a frequency of 0.773 in 1,613,634 control chromosomes in the GnomAD database, including 494,258 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. P234P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.64 (35608 hom., cov: 32)
  • Exomes 𝑓: 0.79 (458650 hom.)
• Consequence: ALK NM_004304.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.80
• Publications: 36 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-29717663-A-T is Benign according to our data. Variant chr2-29717663-A-T is described in ClinVar as Benign. ClinVar VariationId is 259274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.702T>A	p.Pro234Pro	synonymous_variant	Exon 2 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.1629T>A		non_coding_transcript_exon_variant	Exon 2 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.702T>A	p.Pro234Pro	synonymous_variant	Exon 2 of 29	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.-430T>A		5_prime_UTR_variant	Exon 1 of 28	5		ENSP00000482733.1

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97210 AN: 151990 Hom.: 35610 Cov.: 32

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.917

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.823

Gnomad EAS AF: 0.764

Gnomad SAS AF: 0.707

Gnomad FIN AF: 0.737

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.813

Gnomad OTH AF: 0.707

GnomAD2 exomes AF: 0.741 AC: 186258 AN: 251412 AF XY: 0.750

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.729

Gnomad ASJ exome AF: 0.820

Gnomad EAS exome AF: 0.745

Gnomad FIN exome AF: 0.747

Gnomad NFE exome AF: 0.814

Gnomad OTH exome AF: 0.782

GnomAD4 exome AF: 0.786 AC: 1149377 AN: 1461526 Hom.: 458650 Cov.: 47 AF XY: 0.786 AC XY: 571704 AN XY: 727086

African (AFR) AF: 0.224 AC: 7505 AN: 33478

American (AMR) AF: 0.730 AC: 32645 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.824 AC: 21521 AN: 26132

East Asian (EAS) AF: 0.785 AC: 31156 AN: 39692

South Asian (SAS) AF: 0.711 AC: 61290 AN: 86246

European-Finnish (FIN) AF: 0.752 AC: 40145 AN: 53412

Middle Eastern (MID) AF: 0.788 AC: 4543 AN: 5766

European-Non Finnish (NFE) AF: 0.813 AC: 904177 AN: 1111696

Other (OTH) AF: 0.768 AC: 46395 AN: 60382

GnomAD4 genome AF: 0.639 AC: 97206 AN: 152108 Hom.: 35608 Cov.: 32 AF XY: 0.640 AC XY: 47592 AN XY: 74338

African (AFR) AF: 0.250 AC: 10379 AN: 41500

American (AMR) AF: 0.720 AC: 11003 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.823 AC: 2856 AN: 3472

East Asian (EAS) AF: 0.763 AC: 3941 AN: 5164

South Asian (SAS) AF: 0.706 AC: 3393 AN: 4808

European-Finnish (FIN) AF: 0.737 AC: 7785 AN: 10570

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.813 AC: 55300 AN: 67998

Other (OTH) AF: 0.710 AC: 1501 AN: 2114

Alfa AF: 0.762 Hom.: 12215

Bravo AF: 0.622

Asia WGS AF: 0.734 AC: 2553 AN: 3478

EpiCase AF: 0.815

EpiControl AF: 0.824

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:6

Jan 13, 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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

Mar 02, 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

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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 variant of interest causes a synonymous change involving a conserved nucleotide with 5/5 in silico programs via Alamut predicting no significant effect on splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 89037/121392 (34225 homozygotes) indicating that the variant of interest is the major allele (allele most commonly observed in the general population). Therefore, the variant of interest is classified as Benign. -

Hereditary cancer-predisposing syndrome Benign:1

Dec 08, 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	-0.56
CADD	Benign	8.0
DANN	Benign	0.50
PhyloP100		3.8
PromoterAI		-0.0054	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2246745; hg19: chr2-29940529; COSMIC: COSV66584548;