Variant 2-29228936-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_004304.5(ALK):c.2763C>G(p.Phe921Leu) variant causes a missense change. Variant has been reported in ClinVar as Benign (★). 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

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.85

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP6

Variant 2-29228936-G-C is Benign according to our data. Variant chr2-29228936-G-C is described in ClinVar as [Benign]. Clinvar id is 1319121.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-29228936-G-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5 linkuse as main transcript	c.2763C>G	p.Phe921Leu	missense_variant	16/29	ENST00000389048.8
ALK	XR_001738688.3 linkuse as main transcript	n.3668+22C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8 linkuse as main transcript	c.2763C>G	p.Phe921Leu	missense_variant	16/29	1	NM_004304.5	P1
ALK	ENST00000618119.4 linkuse as main transcript	c.1632C>G	p.Phe544Leu	missense_variant	15/28	5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

421

AN:

40644

Hom.:

Cov.:

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.:

Cov.:

AF XY:

0.0696

AC XY:

15288

AN XY:

219614

show subpopulations

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.:

Cov.:

AF XY:

0.00998

AC XY:

201

AN XY:

20150

show subpopulations

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.:

ExAC

AF:

0.0000660

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 03, 2021

- -

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

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;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.75

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over