2-29349433-A-G

Variant names:

• chr2-29349433-A-G
• rs12996631
• NM_004304.5:c.1283-20952T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_004304.5(ALK):​c.1283-20952T>C variant causes a intron change. The variant allele was found at a frequency of 0.365 in 152,086 control chromosomes in the GnomAD database, including 10,479 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.36 (10479 hom., cov: 32)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• neuroblastoma, susceptibility to, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000286963 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.1283-20952T>C		intron_variant	Intron 5 of 28	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.2210-20952T>C		intron_variant	Intron 5 of 17
LOC101929386	XR_007086263.1	n.448-2027A>G		intron_variant	Intron 3 of 4
LOC101929386	XR_939920.3	n.851-731A>G		intron_variant	Intron 7 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.1283-20952T>C		intron_variant	Intron 5 of 28	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.152-20952T>C		intron_variant	Intron 4 of 27	5		ENSP00000482733.1
ENSG00000286963	ENST00000655343.1	n.292-2027A>G		intron_variant	Intron 3 of 4
ENSG00000286963	ENST00000731703.1	n.381-2027A>G		intron_variant	Intron 4 of 6

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55368 AN: 151968 Hom.: 10448 Cov.: 32

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.386

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.365 AC: 55450 AN: 152086 Hom.: 10479 Cov.: 32 AF XY: 0.366 AC XY: 27224 AN XY: 74368

African (AFR) AF: 0.285 AC: 11809 AN: 41474

American (AMR) AF: 0.385 AC: 5877 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1441 AN: 3468

East Asian (EAS) AF: 0.231 AC: 1194 AN: 5170

South Asian (SAS) AF: 0.535 AC: 2580 AN: 4822

European-Finnish (FIN) AF: 0.379 AC: 4003 AN: 10574

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.400 AC: 27222 AN: 67988

Other (OTH) AF: 0.384 AC: 810 AN: 2110

Alfa AF: 0.381 Hom.: 14712

Bravo AF: 0.356

Asia WGS AF: 0.400 AC: 1390 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Benign	0.69
PhyloP100		4.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs12996631; hg19: chr2-29572299;