2-29193615-T-C

Variant names:

• chr2-29193615-T-C
• rs1881420
• NM_004304.5:c.4472A>G

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.4472A>G​(p.Lys1491Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,614,050 control chromosomes in the GnomAD database, including 66,530 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1491Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.28 (7126 hom., cov: 33)
  • Exomes 𝑓: 0.26 (59404 hom.)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:14 O:1
• Conservation: PhyloP100: 1.81
• Publications: 80 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 (MetaRNN=2.522982E-6).
• BP6: Variant 2-29193615-T-C is Benign according to our data. Variant chr2-29193615-T-C is described in ClinVar as Benign. ClinVar VariationId is 133474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.716 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.4472A>G	p.Lys1491Arg	missense	Exon 29 of 29	NP_004295.2
	ALK	NM_001353765.2		c.1268A>G	p.Lys423Arg	missense	Exon 10 of 10	NP_001340694.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.4472A>G	p.Lys1491Arg	missense	Exon 29 of 29	ENSP00000373700.3
	ALK	ENST00000638605.1	TSL:1	n.1349A>G		non_coding_transcript_exon	Exon 11 of 11
	ALK	ENST00000618119.4	TSL:5	c.3341A>G	p.Lys1114Arg	missense	Exon 28 of 28	ENSP00000482733.1

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42416 AN: 152054 Hom.: 7110 Cov.: 33

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.735

Gnomad SAS AF: 0.438

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.273

GnomAD2 exomes AF: 0.344 AC: 86397 AN: 251410 AF XY: 0.334

Gnomad AFR exome AF: 0.249

Gnomad AMR exome AF: 0.588

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.747

Gnomad FIN exome AF: 0.304

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.282

GnomAD4 exome AF: 0.260 AC: 380632 AN: 1461878 Hom.: 59404 Cov.: 73 AF XY: 0.262 AC XY: 190851 AN XY: 727240

African (AFR) AF: 0.247 AC: 8256 AN: 33478

American (AMR) AF: 0.563 AC: 25197 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 4531 AN: 26134

East Asian (EAS) AF: 0.727 AC: 28843 AN: 39700

South Asian (SAS) AF: 0.419 AC: 36106 AN: 86258

European-Finnish (FIN) AF: 0.302 AC: 16121 AN: 53420

Middle Eastern (MID) AF: 0.206 AC: 1188 AN: 5768

European-Non Finnish (NFE) AF: 0.220 AC: 244208 AN: 1112000

Other (OTH) AF: 0.268 AC: 16182 AN: 60396

GnomAD4 genome AF: 0.279 AC: 42458 AN: 152172 Hom.: 7126 Cov.: 33 AF XY: 0.291 AC XY: 21664 AN XY: 74374

African (AFR) AF: 0.247 AC: 10274 AN: 41528

American (AMR) AF: 0.425 AC: 6505 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 616 AN: 3472

East Asian (EAS) AF: 0.736 AC: 3796 AN: 5160

South Asian (SAS) AF: 0.438 AC: 2111 AN: 4824

European-Finnish (FIN) AF: 0.306 AC: 3239 AN: 10598

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14908 AN: 67986

Other (OTH) AF: 0.280 AC: 591 AN: 2110

Alfa AF: 0.247 Hom.: 23828

Bravo AF: 0.291

TwinsUK AF: 0.200 AC: 742

ALSPAC AF: 0.223 AC: 861

ESP6500AA AF: 0.242 AC: 1068

ESP6500EA AF: 0.214 AC: 1837

ExAC AF: 0.332 AC: 40280

Asia WGS AF: 0.578 AC: 2009 AN: 3478

EpiCase AF: 0.217

EpiControl AF: 0.220

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Neuroblastoma, susceptibility to, 3 (6)
-	-	5	not specified (6)
-	-	2	not provided (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
1	-	-	Squamous cell lung carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.8
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.088
Sift	Benign	0.41	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.035
MPC		0.14
ClinPred		0.0063	T
GERP RS		1.9
Varity_R		0.036
gMVP		0.19
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1881420; hg19: chr2-29416481; COSMIC: COSV66555753; COSMIC: COSV66555753;