rs35228363

Positions:

chr2-29275101-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004304.5(ALK):c.2039C>T(p.Thr680Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0232 in 1,614,040 control chromosomes in the GnomAD database, including 542 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 19 hom., cov: 32)

Exomes 𝑓: 0.024 ( 523 hom. )

Consequence

ALK
NM_004304.5 missense, splice_region

Scores

Splicing: ADA: 0.9780

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 4.56

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 (MetaRNN=0.0070204437).

BP6

Variant 2-29275101-G-A is Benign according to our data. Variant chr2-29275101-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 133462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-29275101-G-A is described in Lovd as [Benign]. Variant chr2-29275101-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0157 (2390/152290) while in subpopulation NFE AF= 0.0244 (1663/68018). AF 95% confidence interval is 0.0235. There are 19 homozygotes in gnomad4. There are 1083 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2390 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALK	NM_004304.5 linkuse as main transcript	c.2039C>T	p.Thr680Ile	missense_variant, splice_region_variant	11/29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3 linkuse as main transcript	n.2966C>T		splice_region_variant, non_coding_transcript_exon_variant	11/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8 linkuse as main transcript	c.2039C>T	p.Thr680Ile	missense_variant, splice_region_variant	11/29	1	NM_004304.5	ENSP00000373700	P1
ALK	ENST00000618119.4 linkuse as main transcript	c.908C>T	p.Thr303Ile	missense_variant, splice_region_variant	10/28	5		ENSP00000482733

Frequencies

GnomAD3 genomes

AF:

0.0157

AC:

2390

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00524

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.0199

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0244

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0163

AC:

4104

AN:

251472

Hom.:

AF XY:

0.0168

AC XY:

2284

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00412

Gnomad AMR exome

AF:

0.0108

Gnomad ASJ exome

AF:

0.00923

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00447

Gnomad FIN exome

AF:

0.0204

Gnomad NFE exome

AF:

0.0251

Gnomad OTH exome

AF:

0.0213

GnomAD4 exome

AF:

0.0239

AC:

34991

AN:

1461750

Hom.:

523

Cov.:

AF XY:

0.0236

AC XY:

17133

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.00352

Gnomad4 AMR exome

AF:

0.0116

Gnomad4 ASJ exome

AF:

0.00849

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00425

Gnomad4 FIN exome

AF:

0.0195

Gnomad4 NFE exome

AF:

0.0283

Gnomad4 OTH exome

AF:

0.0209

GnomAD4 genome

AF:

0.0157

AC:

2390

AN:

152290

Hom.:

Cov.:

AF XY:

0.0145

AC XY:

1083

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00522

Gnomad4 AMR

AF:

0.0131

Gnomad4 ASJ

AF:

0.00864

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00518

Gnomad4 FIN

AF:

0.0199

Gnomad4 NFE

AF:

0.0244

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0232

Hom.:

Bravo

AF:

0.0156

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0319

AC:

123

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.0291

AC:

250

ExAC

AF:

0.0159

AC:

1925

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0261

EpiControl

AF:

0.0261

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3

Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not specified

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2016	Variant summary: The ALK c.2039C>T (p.Thr680Ile) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1947/122770 control chromosomes (22 homozygotes) at a frequency of 0.0158589, which is approximately 38061 times the estimated maximal expected allele frequency of a pathogenic ALK variant (0.0000004) based on the disease prevalence of neuroblastoma (susceptibility phenotype), suggesting this variant is likely a benign polymorphism. This variant has been reported in patients with breast cancer and prostate cancer as a germline variant and in patients with hemangioblastoma as a somatic variant; however without strong evidence for pathogenicity (Haiman_2013, Harismendy _2013, Shankar_2014). In a large case-control study that included patients with prostate cancer from multiple ethnicities (African American, Native Hawaiian, Japanese American, Latino and European American), it did not confer an increased risk for prostate cancer in the overall population (Haiman_2013). However, in African American subpopulation, it conferred an elevated risk (odd ratio: 3.104; p-value 0.00025), suggesting that it may confer an ethnicity-specific risk. More reproducible case-control studies are required to confirm this risk association. In ClinVar, one clinical lab has classified it as uncertain significance. Taken together, this variant is currently classified as likely benign. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2016

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

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

0.022

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.73

T;T

MetaRNN

Benign

0.0070

T;T

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.1

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.2

N;.

REVEL

Benign

0.27

Sift

Benign

0.11

T;.

Sift4G

Benign

0.50

T;T

Polyphen

0.078

B;.

Vest4

0.40

MPC

0.39

ClinPred

0.014

GERP RS

5.2

Varity_R

0.10

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Benign

0.55

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