rs138668699

chr2-29229023-G-Achr2-29229023-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004304.5(ALK):c.2676C>T(p.Ala892=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,601,550 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0011 (9 hom.)
• Consequence: ALK NM_004304.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0200

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 2-29229023-G-A is Benign according to our data. Variant chr2-29229023-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 239811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00159 (227/142578) while in subpopulation EAS AF= 0.0044 (21/4774). AF 95% confidence interval is 0.00295. There are 0 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 227 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5	c.2676C>T	p.Ala892=	synonymous_variant	16/29	ENST00000389048.8
ALK	XR_001738688.3	n.3603C>T		non_coding_transcript_exon_variant	16/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.2676C>T	p.Ala892=	synonymous_variant	16/29	1	NM_004304.5	P1
ALK	ENST00000618119.4	c.1545C>T	p.Ala515=	synonymous_variant	15/28	5

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 227 AN: 142506 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000310

Gnomad ASJ AF: 0.00725

Gnomad EAS AF: 0.00439

Gnomad SAS AF: 0.000221

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000553

Gnomad OTH AF: 0.00254

GnomAD3 exomes AF: 0.00220 AC: 554 AN: 251330 Hom.: 2 AF XY: 0.00198 AC XY: 269 AN XY: 135848

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00923

Gnomad EAS exome AF: 0.00256

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.000801

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00112 AC: 1639 AN: 1458972 Hom.: 9 Cov.: 34 AF XY: 0.00108 AC XY: 784 AN XY: 725720

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00794

Gnomad4 EAS exome AF: 0.00578

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.0123

Gnomad4 NFE exome AF: 0.000361

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00159 AC: 227 AN: 142578 Hom.: 0 Cov.: 30 AF XY: 0.00200 AC XY: 137 AN XY: 68502

Gnomad4 AFR AF: 0.000315

Gnomad4 AMR AF: 0.000310

Gnomad4 ASJ AF: 0.00725

Gnomad4 EAS AF: 0.00440

Gnomad4 SAS AF: 0.000222

Gnomad4 FIN AF: 0.0139

Gnomad4 NFE AF: 0.000553

Gnomad4 OTH AF: 0.00252

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.000593

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Invitae	Feb 01, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ALK: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2020	- -

ALK-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2017

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
BayesDel_noAF	Benign	-0.39
Cadd	Benign	8.9
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs138668699; hg19: chr2-29451889;