Genetic Variant ALK:p.Val567Leu (chr2-29297006-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004304.5(ALK):c.1699G>C(p.Val567Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V567G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

ALK
NM_004304.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.251

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18433893).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5 link	c.1699G>C	p.Val567Leu	missense_variant	Exon 9 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3 link	n.2626G>C		non_coding_transcript_exon_variant	Exon 9 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ALK	ENST00000389048.8 link	c.1699G>C	p.Val567Leu	missense_variant	Exon 9 of 29	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4 link	c.568G>C	p.Val190Leu	missense_variant	Exon 8 of 28	5		ENSP00000482733.1
ALK	ENST00000498037.1 link	n.254G>C		non_coding_transcript_exon_variant	Exon 3 of 5	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.070

T;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.0072

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.5

L;.

PhyloP100

-0.25

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.080

N;.

REVEL

Benign

0.053

Sift

Benign

0.62

T;.

Sift4G

Benign

0.63

T;T

Polyphen

0.0010

B;.

Vest4

0.33

MutPred

0.52

Gain of sheet (P = 0.0344);.;

MVP

0.35

MPC

0.17

ClinPred

0.041

GERP RS

-3.3

Varity_R

0.12

gMVP

0.50

Mutation Taster

=89/11

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over