2-29228936-G-C

Variant names:

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 4.85

Publications

10 publications found

Variant links:

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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ALK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5 link	c.2763C>G	p.Phe921Leu	missense_variant	Exon 16 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3 link	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 link	c.2763C>G	p.Phe921Leu	missense_variant	Exon 16 of 29	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4 link	c.1632C>G	p.Phe544Leu	missense_variant	Exon 15 of 28	5		ENSP00000482733.1

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

421

AN:

40644

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.0696

AC XY:

15288

AN XY:

219614

show subpopulations

⚠️ 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:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.313

Heterozygous variant carriers

1661

3322

4983

6644

8305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

158

316

474

632

790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0104

AC:

422

AN:

40726

Hom.:

Cov.:

AF XY:

0.00998

AC XY:

201

AN XY:

20150

show subpopulations

⚠️ 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:

AN:

4510

Ashkenazi Jewish (ASJ)

AF:

0.0143

AC:

AN:

912

East Asian (EAS)

AF:

0.00205

AC:

AN:

1460

South Asian (SAS)

AF:

0.0105

AC:

AN:

1044

European-Finnish (FIN)

AF:

0.0153

AC:

AN:

3016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00956

AC:

172

AN:

17984

Other (OTH)

AF:

0.0254

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.258

Heterozygous variant carriers

106

160

213

266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000481

Hom.:

ExAC

AF:

0.0000660

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

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

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

T;D

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Uncertain

-0.17

MutationAssessor

Pathogenic

3.4

M;.

PhyloP100

4.9

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-4.1

D;.

REVEL

Uncertain

0.32

Sift

Benign

0.36

T;.

Sift4G

Uncertain

0.0030

D;D

Vest4

0.76

ClinPred

0.042

GERP RS

5.2

Varity_R

0.42

gMVP

0.83

Mutation Taster

=60/40

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over