2-29228936-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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).

• 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 id is 1319121.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}. Variant chr2-29228936-G-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.2763C>G	p.Phe921Leu	missense_variant	Exon 16 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.3668+22C>G		intron_variant	Intron 16 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.2763C>G	p.Phe921Leu	missense_variant	Exon 16 of 29	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.1632C>G	p.Phe544Leu	missense_variant	Exon 15 of 28	5		ENSP00000482733.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 421 AN: 40644 Hom.: 0 Cov.: 0 FAILED QC

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

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

Gnomad4 AFR exome AF: 0.0857

Gnomad4 AMR exome AF: 0.0977

Gnomad4 ASJ exome AF: 0.0555

Gnomad4 EAS exome AF: 0.0545

Gnomad4 SAS exome AF: 0.174

Gnomad4 FIN exome AF: 0.0353

Gnomad4 NFE exome AF: 0.0554

Gnomad4 OTH exome AF: 0.0669

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

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.00953

Gnomad4 ASJ AF: 0.0143

Gnomad4 EAS AF: 0.00205

Gnomad4 SAS AF: 0.0105

Gnomad4 FIN AF: 0.0153

Gnomad4 NFE AF: 0.00956

Gnomad4 OTH AF: 0.0254

Alfa AF: 0.000481 Hom.: 0

ExAC AF: 0.0000660 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Jul 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F921L variant (also known as c.2763C>G), located in coding exon 16 of the ALK gene, results from a C to G substitution at nucleotide position 2763. The phenylalanine at codon 921 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided Benign:1

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.4	M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.1	D;.
REVEL	Uncertain	0.32
Sift	Benign	0.36	T;.
Sift4G	Uncertain	0.0030	D;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

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

Publications

LitVar

Other links and lift over

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