2-29214035-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

The NM_004304.5(ALK):c.3692G>A(p.Arg1231Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,613,992 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1231W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.40

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 -5 ACMG points.

• PM1: In a domain Protein kinase (size 276) in uniprot entity ALK_HUMAN there are 30 pathogenic changes around while only 6 benign (83%) in NM_004304.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.07342175).
• BP6: Variant 2-29214035-C-T is Benign according to our data. Variant chr2-29214035-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 404363.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
• BS2: High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5	c.3692G>A	p.Arg1231Gln	missense_variant	24/29	ENST00000389048.8
ALK	NM_001353765.2	c.488G>A	p.Arg163Gln	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.3692G>A	p.Arg1231Gln	missense_variant	24/29	1	NM_004304.5	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000187 AC: 47 AN: 251400 Hom.: 0 AF XY: 0.000213 AC XY: 29 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000103 AC: 150 AN: 1461802 Hom.: 0 Cov.: 31 AF XY: 0.000106 AC XY: 77 AN XY: 727204

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000412

Gnomad4 NFE exome AF: 0.0000971

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74404

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000140 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 06, 2020	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 18, 2021	- -

Neuroblastoma, susceptibility to, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1231 of the ALK protein (p.Arg1231Gln). This variant is present in population databases (rs200110351, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with neuroblastoma (PMID: 25517749). ClinVar contains an entry for this variant (Variation ID: 404363). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect ALK function (PMID: 25517749, 25874976). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 21, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed among individuals with neuroblastoma (Bresler et al., 2014); Published functional studies are inconclusive: variant demonstrated sensitivity to an ALK inhibitor and phosphorylation of a downstream target was reduced, but auto-phosphorylation and foci formation in NIH 3T3 cells were similar to wildtype (Bresler et al., 2014; Lovisa et al., 2015); This variant is associated with the following publications: (PMID: 20719933, 25874976, 25517749) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.036	T;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.073	T;T;T
MetaSVM	Benign	-0.33	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.32	T
Polyphen		0.027	.;B;.
Vest4		0.42, 0.41
MVP		0.80
MPC		0.20
ClinPred		0.086	T
GERP RS		2.9
Varity_R		0.32
gMVP		0.72

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: rs200110351; hg19: chr2-29436901; COSMIC: COSV66558755;