rs4622670

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004304.5(ALK):c.3359+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,613,208 control chromosomes in the GnomAD database, including 91,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 6046 hom., cov: 32)

Exomes 𝑓: 0.33 ( 85073 hom. )

Consequence

ALK
NM_004304.5 splice_donor_region, intron

Scores

Splicing: ADA: 0.00005905

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.20

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 2-29223336-G-A is Benign according to our data. Variant chr2-29223336-G-A is described in ClinVar as [Benign]. Clinvar id is 259271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-29223336-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.35 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.3359+6C>T		splice_donor_region_variant, intron_variant		ENST00000389048.8
ALK	NM_001353765.2 linkuse as main transcript	c.155+6C>T		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8 linkuse as main transcript	c.3359+6C>T		splice_donor_region_variant, intron_variant		1	NM_004304.5	P1

Frequencies

GnomAD3 genomes

AF:

0.246

AC:

37338

AN:

152028

Hom.:

6039

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0628

Gnomad AMI

AF:

0.180

Gnomad AMR

AF:

0.198

Gnomad ASJ

AF:

0.374

Gnomad EAS

AF:

0.0404

Gnomad SAS

AF:

0.349

Gnomad FIN

AF:

0.348

Gnomad MID

AF:

0.334

Gnomad NFE

AF:

0.354

Gnomad OTH

AF:

0.256

GnomAD3 exomes

AF:

0.285

AC:

71325

AN:

250108

Hom.:

12079

AF XY:

0.301

AC XY:

40714

AN XY:

135276

show subpopulations

Gnomad AFR exome

AF:

0.0547

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.380

Gnomad EAS exome

AF:

0.0376

Gnomad SAS exome

AF:

0.360

Gnomad FIN exome

AF:

0.352

Gnomad NFE exome

AF:

0.354

Gnomad OTH exome

AF:

0.300

GnomAD4 exome

AF:

0.331

AC:

483731

AN:

1461062

Hom.:

85073

Cov.:

AF XY:

0.334

AC XY:

242802

AN XY:

726880

show subpopulations

Gnomad4 AFR exome

AF:

0.0529

Gnomad4 AMR exome

AF:

0.167

Gnomad4 ASJ exome

AF:

0.379

Gnomad4 EAS exome

AF:

0.0328

Gnomad4 SAS exome

AF:

0.362

Gnomad4 FIN exome

AF:

0.349

Gnomad4 NFE exome

AF:

0.353

Gnomad4 OTH exome

AF:

0.310

GnomAD4 genome

AF:

0.245

AC:

37334

AN:

152146

Hom.:

6046

Cov.:

AF XY:

0.242

AC XY:

18022

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0626

Gnomad4 AMR

AF:

0.198

Gnomad4 ASJ

AF:

0.374

Gnomad4 EAS

AF:

0.0401

Gnomad4 SAS

AF:

0.351

Gnomad4 FIN

AF:

0.348

Gnomad4 NFE

AF:

0.354

Gnomad4 OTH

AF:

0.251

Alfa

AF:

0.318

Hom.:

10591

Bravo

AF:

0.221

Asia WGS

AF:

0.156

AC:

541

AN:

3478

EpiCase

AF:

0.343

EpiControl

AF:

0.343

ClinVar

Significance: Benign

Submissions summary: Benign:8

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

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 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 ALK c.3359+6C>T variant affects a non-conserved intronic nucleotide. Mutation Taster predicts the variant is a polymorphism, and 5/5 Alamut algorithms predict no significant changes to splicing. This variant was found in 35057/121070 control chromosomes (6051 homozygotes) at a frequency of 0.2895598, which is about 694943 times the maximal expected frequency of a pathogenic ALK allele (0.0000004), suggesting this variant is benign. Taken together, this variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.18

DANN

Benign

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000059

dbscSNV1_RF

Benign

0.012

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