2-29193928-G-A

Variant names:

• chr2-29193928-G-A
• rs17007646
• NM_004304.5:c.4165-6C>T

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.4165-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,613,500 control chromosomes in the GnomAD database, including 19,122 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3891 hom., cov: 32)
  • Exomes 𝑓: 0.13 (15231 hom.)
• Consequence: ALK NM_004304.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001333
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:8
• Conservation: PhyloP100: 0.888
• Publications: 15 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]

CLIP4 (HGNC:26108): (CAP-Gly domain containing linker protein family member 4) Predicted to enable microtubule plus-end binding activity. Predicted to be involved in cytoplasmic microtubule organization. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-29193928-G-A is Benign according to our data. Variant chr2-29193928-G-A is described in ClinVar as Benign. ClinVar VariationId is 259272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004304.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	NM_004304.5	MANE Select	c.4165-6C>T		splice_region intron	N/A	NP_004295.2
	ALK	NM_001353765.2		c.961-6C>T		splice_region intron	N/A	NP_001340694.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.4165-6C>T		splice_region intron	N/A	ENSP00000373700.3
	ALK	ENST00000638605.1	TSL:1	n.1042-6C>T		splice_region intron	N/A
	ALK	ENST00000618119.4	TSL:5	c.3034-6C>T		splice_region intron	N/A	ENSP00000482733.1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29870 AN: 152042 Hom.: 3890 Cov.: 32

Gnomad AFR AF: 0.368

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0346

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.178

GnomAD2 exomes AF: 0.125 AC: 31187 AN: 249008 AF XY: 0.120

Gnomad AFR exome AF: 0.376

Gnomad AMR exome AF: 0.0728

Gnomad ASJ exome AF: 0.143

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.133 AC: 193813 AN: 1461340 Hom.: 15231 Cov.: 35 AF XY: 0.130 AC XY: 94225 AN XY: 726994

African (AFR) AF: 0.379 AC: 12696 AN: 33464

American (AMR) AF: 0.0810 AC: 3621 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3712 AN: 26122

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0422 AC: 3634 AN: 86210

European-Finnish (FIN) AF: 0.184 AC: 9810 AN: 53394

Middle Eastern (MID) AF: 0.126 AC: 727 AN: 5766

European-Non Finnish (NFE) AF: 0.136 AC: 151551 AN: 1111624

Other (OTH) AF: 0.133 AC: 8059 AN: 60370

GnomAD4 genome AF: 0.196 AC: 29899 AN: 152160 Hom.: 3891 Cov.: 32 AF XY: 0.193 AC XY: 14364 AN XY: 74402

African (AFR) AF: 0.368 AC: 15263 AN: 41470

American (AMR) AF: 0.127 AC: 1937 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 498 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0344 AC: 166 AN: 4824

European-Finnish (FIN) AF: 0.191 AC: 2019 AN: 10590

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9463 AN: 68000

Other (OTH) AF: 0.177 AC: 373 AN: 2112

Alfa AF: 0.181 Hom.: 3913

Bravo AF: 0.201

Asia WGS AF: 0.0370 AC: 131 AN: 3478

EpiCase AF: 0.133

EpiControl AF: 0.136

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Apr 05, 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

Sep 10, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Neuroblastoma, susceptibility to, 3 Benign:3

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.

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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 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 is located at a non-conserved intronic position, not widely known to affect splicing, with 4/5 in silico programs via Alamut predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 15272/116488 (1/7 including 1465 homozygotes), which exceeds the predicted maximum expected allele frequency for a pathogenic ALK of 1/2500000. The variant of interest, to our knowledge, has not been published in affected individuals. A reputable clinical laboratory cites the variant with a classification of "benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.

Squamous cell lung carcinoma Uncertain:1

May 05, 2020

Faculté Pluridciplinaire Nador, Université Mohamed Premier

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing;in vivo

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.5
DANN	Benign	0.69
PhyloP100		0.89
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0
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: rs17007646; hg19: chr2-29416794; COSMIC: COSV66561728; COSMIC: COSV66561728;