rs17007646

chr2-29193928-G-Achr2-29193928-G-C

Variant summary

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

The NM_004304.5(ALK):c.4165-6C>T variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001333

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:7

Conservation

PhyloP100: 0.888

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:

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]

CLIP4 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=-0.8).

BP6

Variant 2-29193928-G-A is Benign according to our data. Variant chr2-29193928-G-A is described in ClinVar as [Benign]. Clinvar id is 259272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-29193928-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.363 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.4165-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000389048.8
ALK	NM_001353765.2 linkuse as main transcript	c.961-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8 linkuse as main transcript	c.4165-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004304.5	P1

Frequencies

GnomAD3 genomes

AF:

0.196

AC:

29870

AN:

152042

Hom.:

3890

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.125

AC:

31187

AN:

249008

Hom.:

2850

AF XY:

0.120

AC XY:

16241

AN XY:

135182

show subpopulations

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 SAS exome

AF:

0.0413

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.:

AF XY:

0.130

AC XY:

94225

AN XY:

726994

show subpopulations

Gnomad4 AFR exome

AF:

0.379

Gnomad4 AMR exome

AF:

0.0810

Gnomad4 ASJ exome

AF:

0.142

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0422

Gnomad4 FIN exome

AF:

0.184

Gnomad4 NFE exome

AF:

0.136

Gnomad4 OTH exome

AF:

0.133

GnomAD4 genome

AF:

0.196

AC:

29899

AN:

152160

Hom.:

3891

Cov.:

AF XY:

0.193

AC XY:

14364

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.368

Gnomad4 AMR

AF:

0.127

Gnomad4 ASJ

AF:

0.144

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0344

Gnomad4 FIN

AF:

0.191

Gnomad4 NFE

AF:

0.139

Gnomad4 OTH

AF:

0.177

Alfa

AF:

0.163

Hom.:

1952

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:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 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	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 10, 2015	- -

Neuroblastoma, susceptibility to, 3

Benign:3

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	- -
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. -

Squamous cell lung carcinoma

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing;in vivo

Faculté Pluridciplinaire Nador, Université Mohamed Premier

May 05, 2020

- -

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 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

Cadd

Benign

2.5

Dann

Benign

0.69

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

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