2-29193500-G-C

Variant names:

• chr2-29193500-G-C
• rs1881421
• NM_004304.5:c.4587C>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.4587C>G​(p.Asp1529Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 1,613,842 control chromosomes in the GnomAD database, including 137,955 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. D1529N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.48 (18503 hom., cov: 32)
  • Exomes 𝑓: 0.39 (119452 hom.)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:16 O:1
• Conservation: PhyloP100: -0.102
• Publications: 70 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=1.4798009E-6).
• BP6: Variant 2-29193500-G-C is Benign according to our data. Variant chr2-29193500-G-C is described in ClinVar as Benign. ClinVar VariationId is 133476.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.4587C>G	p.Asp1529Glu	missense	Exon 29 of 29	NP_004295.2
	ALK	NM_001353765.2		c.1383C>G	p.Asp461Glu	missense	Exon 10 of 10	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.4587C>G	p.Asp1529Glu	missense	Exon 29 of 29	ENSP00000373700.3	Q9UM73
	ALK	ENST00000638605.1	TSL:1	n.1464C>G		non_coding_transcript_exon	Exon 11 of 11
	ALK	ENST00000618119.4	TSL:5	c.3456C>G	p.Asp1152Glu	missense	Exon 28 of 28	ENSP00000482733.1	A0A087WZL3

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72103 AN: 151896 Hom.: 18456 Cov.: 32

Gnomad AFR AF: 0.616

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.549

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.735

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.496

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.453

GnomAD2 exomes AF: 0.468 AC: 117649 AN: 251122 AF XY: 0.454

Gnomad AFR exome AF: 0.626

Gnomad AMR exome AF: 0.660

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.746

Gnomad FIN exome AF: 0.490

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.417

GnomAD4 exome AF: 0.392 AC: 573213 AN: 1461828 Hom.: 119452 Cov.: 67 AF XY: 0.391 AC XY: 284364 AN XY: 727214

African (AFR) AF: 0.623 AC: 20872 AN: 33476

American (AMR) AF: 0.643 AC: 28778 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 8068 AN: 26136

East Asian (EAS) AF: 0.726 AC: 28820 AN: 39700

South Asian (SAS) AF: 0.455 AC: 39210 AN: 86256

European-Finnish (FIN) AF: 0.485 AC: 25902 AN: 53420

Middle Eastern (MID) AF: 0.332 AC: 1915 AN: 5768

European-Non Finnish (NFE) AF: 0.356 AC: 395459 AN: 1111952

Other (OTH) AF: 0.401 AC: 24189 AN: 60396

GnomAD4 genome AF: 0.475 AC: 72209 AN: 152014 Hom.: 18503 Cov.: 32 AF XY: 0.485 AC XY: 36007 AN XY: 74314

African (AFR) AF: 0.616 AC: 25538 AN: 41454

American (AMR) AF: 0.550 AC: 8399 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1094 AN: 3464

East Asian (EAS) AF: 0.735 AC: 3798 AN: 5166

South Asian (SAS) AF: 0.466 AC: 2240 AN: 4806

European-Finnish (FIN) AF: 0.496 AC: 5240 AN: 10574

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24337 AN: 67948

Other (OTH) AF: 0.458 AC: 967 AN: 2112

Alfa AF: 0.378 Hom.: 8704

Bravo AF: 0.490

TwinsUK AF: 0.341 AC: 1264

ALSPAC AF: 0.367 AC: 1413

ESP6500AA AF: 0.608 AC: 2681

ESP6500EA AF: 0.344 AC: 2957

ExAC AF: 0.460 AC: 55843

Asia WGS AF: 0.613 AC: 2132 AN: 3478

EpiCase AF: 0.350

EpiControl AF: 0.355

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	Neuroblastoma, susceptibility to, 3 (8)
-	-	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	0.060
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.041
DANN	Benign	0.59
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00049	N
LIST_S2	Benign	0.053	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-0.10
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.063
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.015
MutPred		0.097		Loss of catalytic residue at D1529 (P = 0.0319)
MPC		0.16
ClinPred		0.0045	T
GERP RS		-3.4
Varity_R		0.026
gMVP		0.061
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: rs1881421; hg19: chr2-29416366; COSMIC: COSV66569695; COSMIC: COSV66569695;