rs4622670

Variant names:

• chr2-29223336-G-A
• rs4622670
• NM_004304.5:c.3359+6C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-29223336-G-A
• chr2-29223336-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004304.5(ALK):​c.3359+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,613,208 control chromosomes in the GnomAD database, including 91,119 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6046 hom., cov: 32)
  • Exomes 𝑓: 0.33 (85073 hom.)
• Consequence: ALK NM_004304.5 splice_region, intron
• Scores: Splicing: ADA: 0.00005905
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.20
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 2-29223336-G-A is Benign according to our data. Variant chr2-29223336-G-A is described in ClinVar as Benign. ClinVar VariationId is 259271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.35 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	NM_004304.5	MANE Select	c.3359+6C>T		splice_region intron	N/A	NP_004295.2
	ALK	NM_001353765.2		c.155+6C>T		splice_region intron	N/A	NP_001340694.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.3359+6C>T		splice_region intron	N/A	ENSP00000373700.3
	ALK	ENST00000638605.1	TSL:1	n.236+6C>T		splice_region intron	N/A
	ALK	ENST00000618119.4	TSL:5	c.2228+6C>T		splice_region intron	N/A	ENSP00000482733.1

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37338 AN: 152028 Hom.: 6039 Cov.: 32

Gnomad AFR AF: 0.0628

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.0404

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.256

GnomAD2 exomes AF: 0.285 AC: 71325 AN: 250108 AF XY: 0.301

Gnomad AFR exome AF: 0.0547

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.380

Gnomad EAS exome AF: 0.0376

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.354

Gnomad OTH exome AF: 0.300

GnomAD4 exome AF: 0.331 AC: 483731 AN: 1461062 Hom.: 85073 Cov.: 38 AF XY: 0.334 AC XY: 242802 AN XY: 726880

African (AFR) AF: 0.0529 AC: 1772 AN: 33474

American (AMR) AF: 0.167 AC: 7460 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 9893 AN: 26130

East Asian (EAS) AF: 0.0328 AC: 1303 AN: 39696

South Asian (SAS) AF: 0.362 AC: 31193 AN: 86240

European-Finnish (FIN) AF: 0.349 AC: 18566 AN: 53182

Middle Eastern (MID) AF: 0.358 AC: 2064 AN: 5768

European-Non Finnish (NFE) AF: 0.353 AC: 392740 AN: 1111486

Other (OTH) AF: 0.310 AC: 18740 AN: 60368

GnomAD4 genome AF: 0.245 AC: 37334 AN: 152146 Hom.: 6046 Cov.: 32 AF XY: 0.242 AC XY: 18022 AN XY: 74366

African (AFR) AF: 0.0626 AC: 2600 AN: 41518

American (AMR) AF: 0.198 AC: 3034 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1298 AN: 3470

East Asian (EAS) AF: 0.0401 AC: 208 AN: 5184

South Asian (SAS) AF: 0.351 AC: 1690 AN: 4816

European-Finnish (FIN) AF: 0.348 AC: 3678 AN: 10576

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.354 AC: 24037 AN: 67982

Other (OTH) AF: 0.251 AC: 528 AN: 2106

Alfa AF: 0.309 Hom.: 12641

Bravo AF: 0.221

Asia WGS AF: 0.156 AC: 541 AN: 3478

EpiCase AF: 0.343

EpiControl AF: 0.343

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Neuroblastoma, susceptibility to, 3 (5)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.18
DANN	Benign	0.78
PhyloP100		-1.2
PromoterAI		0.10	Neutral
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000059
dbscSNV1_RF	Benign	0.012
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: rs4622670; hg19: chr2-29446202; COSMIC: COSV66569119;