chr2-29920310-G-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004304.5(ALK):c.350C>G(p.Pro117Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,559,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

ALK
NM_004304.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 0.809

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:

ENSG00000288553 (HGNC:):

ENSG00000288553 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11254534).

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5 link	c.350C>G	p.Pro117Arg	missense_variant	Exon 1 of 29	ENST00000389048.8	NP_004295.2	Q9UM73B6D4Y2
ALK	XR_001738688.3 link	n.1277C>G		non_coding_transcript_exon_variant	Exon 1 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8 link	c.350C>G	p.Pro117Arg	missense_variant	Exon 1 of 29	1	NM_004304.5	ENSP00000373700.3		Q9UM73
ENSG00000288553	ENST00000669284.1 link	n.157+34939C>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000511

AC:

AN:

156706

Hom.:

AF XY:

0.0000703

AC XY:

AN XY:

85312

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000393

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000125

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000654

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000210

AC:

295

AN:

1406902

Hom.:

Cov.:

AF XY:

0.000200

AC XY:

139

AN XY:

695212

show subpopulations

Gnomad4 AFR exome

AF:

0.0000312

Gnomad4 AMR exome

AF:

0.0000272

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000124

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000258

Gnomad4 OTH exome

AF:

0.0000514

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000850

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000800

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3

Uncertain:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 117 of the ALK protein (p.Pro117Arg). This variant is present in population databases (rs201290745, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ALK-related conditions. ClinVar contains an entry for this variant (Variation ID: 470832). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 21, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ALK c.350C>G (p.Pro117Arg) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with ALK-related neuroblastic tumor susceptibility. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Dec 03, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Sep 03, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided

Uncertain:1

Oct 04, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

Eigen

Benign

-0.022

Eigen_PC

Benign

-0.029

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.54

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.55

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.96

REVEL

Benign

0.064

Sift

Uncertain

0.0070

Sift4G

Pathogenic

0.0

Polyphen

0.93

Vest4

0.078

MVP

0.51

MPC

0.31

ClinPred

0.094

GERP RS

4.5

Varity_R

0.064

gMVP

0.099

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

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