2-29600786-A-G

Position:

• chr2-29600786-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004304.5(ALK):​c.953-68670T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.761 in 152,088 control chromosomes in the GnomAD database, including 44,120 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 0.76 (44120 hom., cov: 32)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.801

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALK	NM_004304.5	c.953-68670T>C		intron_variant		ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.1880-68670T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.953-68670T>C		intron_variant		1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.-179-68670T>C		intron_variant		5		ENSP00000482733.1

Frequencies

GnomAD3 genomes AF: 0.761 AC: 115617 AN: 151970 Hom.: 44077 Cov.: 32

Gnomad AFR AF: 0.779

Gnomad AMI AF: 0.817

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.770

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.785

Gnomad FIN AF: 0.760

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.756

Gnomad OTH AF: 0.756

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

GnomAD4 genome AF: 0.761 AC: 115714 AN: 152088 Hom.: 44120 Cov.: 32 AF XY: 0.760 AC XY: 56520 AN XY: 74360

Gnomad4 AFR AF: 0.779

Gnomad4 AMR AF: 0.726

Gnomad4 ASJ AF: 0.770

Gnomad4 EAS AF: 0.745

Gnomad4 SAS AF: 0.785

Gnomad4 FIN AF: 0.760

Gnomad4 NFE AF: 0.756

Gnomad4 OTH AF: 0.758

Alfa AF: 0.756 Hom.: 21767

Bravo AF: 0.757

Asia WGS AF: 0.793 AC: 2758 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	6.1
DANN	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs4666255; hg19: chr2-29823652;