rs17007646

Variant names:

• chr2-29193928-G-A
• rs17007646
• NM_004304.5:c.4165-6C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-29193928-G-A
• chr2-29193928-G-C
• chr2-29193928-G-T

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.4165-6C>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 0.139 in 1,613,500 control chromosomes in the GnomAD database, including 19,122 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 0.20 (3891 hom., cov: 32)
  • Exomes 𝑓: 0.13 (15231 hom.)
• Consequence: ALK NM_004304.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001333
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:8
• Conservation: PhyloP100: 0.888
• Publications: 15 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]

CLIP4 (HGNC:26108): (CAP-Gly domain containing linker protein family member 4) Predicted to enable microtubule plus-end binding activity. Predicted to be involved in cytoplasmic microtubule organization. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-29193928-G-A is Benign according to our data. Variant chr2-29193928-G-A is described in ClinVar as Benign. ClinVar VariationId is 259272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.363 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.4165-6C>T		splice_region intron	N/A	NP_004295.2
	ALK	NM_001353765.2		c.961-6C>T		splice_region intron	N/A	NP_001340694.1	A0A0K2YUJ3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.4165-6C>T		splice_region intron	N/A	ENSP00000373700.3	Q9UM73
	ALK	ENST00000638605.1	TSL:1	n.1042-6C>T		splice_region intron	N/A
	ALK	ENST00000618119.4	TSL:5	c.3034-6C>T		splice_region intron	N/A	ENSP00000482733.1	A0A087WZL3

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29870 AN: 152042 Hom.: 3890 Cov.: 32

Gnomad AFR AF: 0.368

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0346

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.178

GnomAD2 exomes AF: 0.125 AC: 31187 AN: 249008 AF XY: 0.120

Gnomad AFR exome AF: 0.376

Gnomad AMR exome AF: 0.0728

Gnomad ASJ exome AF: 0.143

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.133 AC: 193813 AN: 1461340 Hom.: 15231 Cov.: 35 AF XY: 0.130 AC XY: 94225 AN XY: 726994

African (AFR) AF: 0.379 AC: 12696 AN: 33464

American (AMR) AF: 0.0810 AC: 3621 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3712 AN: 26122

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0422 AC: 3634 AN: 86210

European-Finnish (FIN) AF: 0.184 AC: 9810 AN: 53394

Middle Eastern (MID) AF: 0.126 AC: 727 AN: 5766

European-Non Finnish (NFE) AF: 0.136 AC: 151551 AN: 1111624

Other (OTH) AF: 0.133 AC: 8059 AN: 60370

GnomAD4 genome AF: 0.196 AC: 29899 AN: 152160 Hom.: 3891 Cov.: 32 AF XY: 0.193 AC XY: 14364 AN XY: 74402

African (AFR) AF: 0.368 AC: 15263 AN: 41470

American (AMR) AF: 0.127 AC: 1937 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 498 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0344 AC: 166 AN: 4824

European-Finnish (FIN) AF: 0.191 AC: 2019 AN: 10590

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9463 AN: 68000

Other (OTH) AF: 0.177 AC: 373 AN: 2112

Alfa AF: 0.181 Hom.: 3913

Bravo AF: 0.201

Asia WGS AF: 0.0370 AC: 131 AN: 3478

EpiCase AF: 0.133

EpiControl AF: 0.136

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Neuroblastoma, susceptibility to, 3 (3)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	1	-	Squamous cell lung carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.5
DANN	Benign	0.69
PhyloP100		0.89
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0
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: rs17007646; hg19: chr2-29416794; COSMIC: COSV66561728; COSMIC: COSV66561728;