rs35228363

chr2-29275101-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Synonymous variant affecting the same amino acid position (i.e. T680T) has been classified 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:10 O:1
• Conservation: PhyloP100: 4.56

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]

ACMG classification

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 GnomAd at 2390 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2390 AN: 152172 Hom.: 19 Cov.: 32

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.: 53 AF XY: 0.0168 AC XY: 2284 AN XY: 135914

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.: 32 AF XY: 0.0236 AC XY: 17133 AN XY: 727176

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.: 19 Cov.: 32 AF XY: 0.0145 AC XY: 1083 AN XY: 74468

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.: 88

Bravo AF: 0.0156

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0319 AC: 123

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0291 AC: 250

ExAC AF: 0.0159 AC: 1925

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.0261

EpiControl AF: 0.0261

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:6

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	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 22, 2016	- -
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:2 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:1

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. -

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	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	0.022
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.73	T;T
MetaRNN	Benign	0.0070	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
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	T
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

Other links and lift over

dbSNP: rs35228363; hg19: chr2-29497967; COSMIC: COSV66555766;