rs140733978

Variant names:

• chr2-29225553-G-A
• rs140733978
• NM_004304.5:c.3080C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-29225553-G-A
• chr2-29225553-G-T
• chr2-29225553-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004304.5(ALK):​c.3080C>T​(p.Pro1027Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,608,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. P1027Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6 O:1
• Conservation: PhyloP100: 2.16
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.051793247).
• BP6: Variant 2-29225553-G-A is Benign according to our data. Variant chr2-29225553-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 133467.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000493 (75/151976) while in subpopulation AFR AF = 0.00149 (62/41486). AF 95% confidence interval is 0.0012. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 75 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.3080C>T	p.Pro1027Leu	missense	Exon 19 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.3080C>T	p.Pro1027Leu	missense	Exon 19 of 29	ENSP00000373700.3	Q9UM73
	ALK	ENST00000618119.4	TSL:5	c.1949C>T	p.Pro650Leu	missense	Exon 18 of 28	ENSP00000482733.1	A0A087WZL3
	ALK	ENST00000431873.6	TSL:5	n.245C>T		non_coding_transcript_exon	Exon 3 of 14	ENSP00000414027.3	E7EPW7

Frequencies

GnomAD3 genomes AF: 0.000494 AC: 75 AN: 151862 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.000133

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000713 AC: 17 AN: 238580 AF XY: 0.0000855

Gnomad AFR exome AF: 0.000722

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000463

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.0000707 AC: 103 AN: 1456808 Hom.: 0 Cov.: 32 AF XY: 0.0000691 AC XY: 50 AN XY: 724092

African (AFR) AF: 0.000897 AC: 30 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25856

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39542

South Asian (SAS) AF: 0.00 AC: 0 AN: 84630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5304

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1110962

Other (OTH) AF: 0.000233 AC: 14 AN: 60156

GnomAD4 genome AF: 0.000493 AC: 75 AN: 151976 Hom.: 0 Cov.: 32 AF XY: 0.000539 AC XY: 40 AN XY: 74248

African (AFR) AF: 0.00149 AC: 62 AN: 41486

American (AMR) AF: 0.000196 AC: 3 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67902

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000215 Hom.: 0

Bravo AF: 0.000412

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000907 AC: 11

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Benign	0.80
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.95	L
PhyloP100		2.2
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.16
Sift	Benign	0.20	T
Sift4G	Benign	0.55	T
Polyphen		0.029	B
Vest4		0.35
MVP		0.66
MPC		0.17
ClinPred		0.033	T
GERP RS		3.8
Varity_R		0.056
gMVP		0.72
Mutation Taster		=99/1	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: rs140733978; hg19: chr2-29448419; COSMIC: COSV66575315;