NM_004304.5:c.952+41373C>T

Variant names:

• chr2-29653477-G-A
• rs7577363
• NM_004304.5:c.952+41373C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004304.5(ALK):​c.952+41373C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0752 in 152,004 control chromosomes in the GnomAD database, including 784 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 0.075 (784 hom., cov: 32)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0480
• Publications: 4 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.952+41373C>T		intron_variant	Intron 3 of 28	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.1879+41373C>T		intron_variant	Intron 3 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.952+41373C>T		intron_variant	Intron 3 of 28	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.-180+41373C>T		intron_variant	Intron 2 of 27	5		ENSP00000482733.1

Frequencies

GnomAD3 genomes AF: 0.0748 AC: 11364 AN: 151886 Hom.: 767 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0416

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.0101

Gnomad SAS AF: 0.0578

Gnomad FIN AF: 0.0530

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0330

Gnomad OTH AF: 0.0614

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

GnomAD4 genome AF: 0.0752 AC: 11432 AN: 152004 Hom.: 784 Cov.: 32 AF XY: 0.0754 AC XY: 5599 AN XY: 74278

African (AFR) AF: 0.179 AC: 7397 AN: 41424

American (AMR) AF: 0.0416 AC: 635 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 81 AN: 3468

East Asian (EAS) AF: 0.0101 AC: 52 AN: 5154

South Asian (SAS) AF: 0.0585 AC: 281 AN: 4802

European-Finnish (FIN) AF: 0.0530 AC: 560 AN: 10576

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0330 AC: 2245 AN: 67994

Other (OTH) AF: 0.0608 AC: 128 AN: 2106

Alfa AF: 0.0542 Hom.: 186

Bravo AF: 0.0770

Asia WGS AF: 0.0410 AC: 141 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.6
DANN	Benign	0.70
PhyloP100		-0.048
Mutation Taster		=100/0	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: rs7577363; hg19: chr2-29876343;