rs112022466

chr2-29227671-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_004304.5(ALK):c.2817C>T(p.Gly939=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,613,428 control chromosomes in the GnomAD database, including 1 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: ALK NM_004304.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.00006324
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.179

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-29227671-G-A is Benign according to our data. Variant chr2-29227671-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 470808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.179 with no splicing effect.
• BS2: High AC in GnomAd at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5	c.2817C>T	p.Gly939=	splice_region_variant, synonymous_variant	17/29	ENST00000389048.8
ALK	XR_001738688.3	n.3670C>T		splice_region_variant, non_coding_transcript_exon_variant	17/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.2817C>T	p.Gly939=	splice_region_variant, synonymous_variant	17/29	1	NM_004304.5	P1
ALK	ENST00000618119.4	c.1686C>T	p.Gly562=	splice_region_variant, synonymous_variant	16/28	5
ALK	ENST00000431873.6			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 251378 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135874

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000133 AC: 195 AN: 1461178 Hom.: 1 Cov.: 31 AF XY: 0.000140 AC XY: 102 AN XY: 726952

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000756

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74446

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000232 Hom.: 1

Bravo AF: 0.000144

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 12, 2022	This alteration is classified as likely 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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 16, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	8.0
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000063
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

Other links and lift over

dbSNP: rs112022466; hg19: chr2-29450537; COSMIC: COSV66580364; COSMIC: COSV66580364;