rs61754865

Variant names:

• chr2-29232359-C-G
• rs61754865
• NM_004304.5:c.2577G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-29232359-C-G
• chr2-29232359-C-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_004304.5(ALK):​c.2577G>C​(p.Glu859Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,614,268 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E859K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., cov: 34)
  • Exomes 𝑓: 0.00013 (2 hom.)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4 O:1
• Conservation: PhyloP100: 1.52
• Publications: 10 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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08712977).
• BP6: Variant 2-29232359-C-G is Benign according to our data. Variant chr2-29232359-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 133464.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00102 (155/152376) while in subpopulation AFR AF = 0.00361 (150/41584). AF 95% confidence interval is 0.00314. There are 2 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 155 AD gene.

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.2577G>C	p.Glu859Asp	missense	Exon 15 of 29	NP_004295.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.2577G>C	p.Glu859Asp	missense	Exon 15 of 29	ENSP00000373700.3	Q9UM73
	ALK	ENST00000618119.4	TSL:5	c.1446G>C	p.Glu482Asp	missense	Exon 14 of 28	ENSP00000482733.1	A0A087WZL3

Frequencies

GnomAD3 genomes AF: 0.000998 AC: 152 AN: 152258 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000262 AC: 66 AN: 251486 AF XY: 0.000155

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000127 AC: 185 AN: 1461892 Hom.: 2 Cov.: 30 AF XY: 0.0000976 AC XY: 71 AN XY: 727248

African (AFR) AF: 0.00412 AC: 138 AN: 33480

American (AMR) AF: 0.000224 AC: 10 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.000480 AC: 29 AN: 60396

GnomAD4 genome AF: 0.00102 AC: 155 AN: 152376 Hom.: 2 Cov.: 34 AF XY: 0.00105 AC XY: 78 AN XY: 74516

African (AFR) AF: 0.00361 AC: 150 AN: 41584

American (AMR) AF: 0.000196 AC: 3 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.0000910 Hom.: 0

Bravo AF: 0.00120

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000272 AC: 33

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	1	not provided (2)
-	-	1	Neuroblastoma, susceptibility to, 3 (1)
-	1	-	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.096	T
Eigen	Benign	0.19
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.087	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.43
Sift	Benign	0.030	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.16		Loss of glycosylation at T855 (P = 0.1456)
MVP		0.85
MPC		0.56
ClinPred		0.041	T
GERP RS		3.1
Varity_R		0.12
gMVP		0.79
Mutation Taster		=93/7	polymorphism

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: rs61754865; hg19: chr2-29455225; COSMIC: COSV66577816;