rs6707371

Variant names:

• chr2-29852538-A-G
• rs6707371
• NM_004304.5:c.667+67455T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-29852538-A-G
• chr2-29852538-A-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.667+67455T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 151,994 control chromosomes in the GnomAD database, including 14,543 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 0.41 (14543 hom., cov: 32)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.817
• Publications: 6 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ENSG00000233862 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004304.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	NM_004304.5	MANE Select	c.667+67455T>C		intron	N/A	NP_004295.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.667+67455T>C		intron	N/A	ENSP00000373700.3	Q9UM73
	ENSG00000233862	ENST00000669284.1		n.158-10901T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62395 AN: 151876 Hom.: 14539 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.776

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.577

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.467

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

GnomAD4 genome AF: 0.411 AC: 62413 AN: 151994 Hom.: 14543 Cov.: 32 AF XY: 0.418 AC XY: 31059 AN XY: 74272

African (AFR) AF: 0.207 AC: 8585 AN: 41456

American (AMR) AF: 0.596 AC: 9104 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1974 AN: 3470

East Asian (EAS) AF: 0.777 AC: 4004 AN: 5154

South Asian (SAS) AF: 0.593 AC: 2847 AN: 4804

European-Finnish (FIN) AF: 0.382 AC: 4026 AN: 10548

Middle Eastern (MID) AF: 0.580 AC: 167 AN: 288

European-Non Finnish (NFE) AF: 0.444 AC: 30201 AN: 67968

Other (OTH) AF: 0.470 AC: 991 AN: 2110

Alfa AF: 0.450 Hom.: 23239

Bravo AF: 0.421

Asia WGS AF: 0.617 AC: 2144 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.44
DANN	Benign	0.73
PhyloP100		-0.82
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: rs6707371; hg19: chr2-30075404;