NM_004304.5:c.2763C>G

Variant names:

• chr2-29228936-G-C
• rs201042802
• NM_004304.5:c.2763C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_004304.5(ALK):​c.2763C>G​(p.Phe921Leu) variant causes a missense change. 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. F921C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (0 hom., cov: 0)
  • Exomes 𝑓: 0.067 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.85
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 2-29228936-G-C is Benign according to our data. Variant chr2-29228936-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1319121.

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.2763C>G	p.Phe921Leu	missense	Exon 16 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.2763C>G	p.Phe921Leu	missense	Exon 16 of 29	ENSP00000373700.3	Q9UM73
	ALK	ENST00000618119.4	TSL:5	c.1632C>G	p.Phe544Leu	missense	Exon 15 of 28	ENSP00000482733.1	A0A087WZL3

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 421 AN: 40644 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00391

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.0143

Gnomad EAS AF: 0.00137

Gnomad SAS AF: 0.0105

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00957

Gnomad OTH AF: 0.0260

GnomAD2 exomes AF: 0.0276 AC: 4651 AN: 168570 AF XY: 0.0259

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.0574

Gnomad ASJ exome AF: 0.0186

Gnomad EAS exome AF: 0.0418

Gnomad FIN exome AF: 0.00873

Gnomad NFE exome AF: 0.0194

Gnomad OTH exome AF: 0.0443

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0670 AC: 28003 AN: 417906 Hom.: 0 Cov.: 14 AF XY: 0.0696 AC XY: 15288 AN XY: 219614

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0857 AC: 898 AN: 10478

American (AMR) AF: 0.0977 AC: 1987 AN: 20348

Ashkenazi Jewish (ASJ) AF: 0.0555 AC: 592 AN: 10672

East Asian (EAS) AF: 0.0545 AC: 965 AN: 17710

South Asian (SAS) AF: 0.174 AC: 6003 AN: 34422

European-Finnish (FIN) AF: 0.0353 AC: 997 AN: 28208

Middle Eastern (MID) AF: 0.0326 AC: 83 AN: 2546

European-Non Finnish (NFE) AF: 0.0554 AC: 15190 AN: 274264

Other (OTH) AF: 0.0669 AC: 1288 AN: 19258

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0104 AC: 422 AN: 40726 Hom.: 0 Cov.: 0 AF XY: 0.00998 AC XY: 201 AN XY: 20150

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0109 AC: 120 AN: 10966

American (AMR) AF: 0.00953 AC: 43 AN: 4510

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 13 AN: 912

East Asian (EAS) AF: 0.00205 AC: 3 AN: 1460

South Asian (SAS) AF: 0.0105 AC: 11 AN: 1044

European-Finnish (FIN) AF: 0.0153 AC: 46 AN: 3016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 66

European-Non Finnish (NFE) AF: 0.00956 AC: 172 AN: 17984

Other (OTH) AF: 0.0254 AC: 13 AN: 512

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000481 Hom.: 0

ExAC AF: 0.0000660 AC: 8

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		4.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.32
Sift	Benign	0.36	T
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.24		Gain of MoRF binding (P = 0.1064)
MPC		0.76
ClinPred		0.042	T
GERP RS		5.2
Varity_R		0.42
gMVP		0.83
Mutation Taster		=60/40	polymorphism

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: rs201042802; hg19: chr2-29451802; COSMIC: COSV101200869; COSMIC: COSV101200869;