chr2-29920191-G-A

Position:

chr2-29920191-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004304.5(ALK):c.469C>T(p.Pro157Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000285 in 1,612,784 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00052 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

ALK
NM_004304.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 2.37

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009894013).

BP6

Variant 2-29920191-G-A is Benign according to our data. Variant chr2-29920191-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 239842.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}. Variant chr2-29920191-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALK	NM_004304.5 linkuse as main transcript	c.469C>T	p.Pro157Ser	missense_variant	1/29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3 linkuse as main transcript	n.1396C>T		non_coding_transcript_exon_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8 linkuse as main transcript	c.469C>T	p.Pro157Ser	missense_variant	1/29	1	NM_004304.5	ENSP00000373700	P1
	ENST00000669284.1 linkuse as main transcript	n.157+35058C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000964

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000823

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000213

AC:

AN:

244624

Hom.:

AF XY:

0.000194

AC XY:

AN XY:

133736

show subpopulations

Gnomad AFR exome

AF:

0.0000684

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000403

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000190

Gnomad NFE exome

AF:

0.000363

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000260

AC:

380

AN:

1460560

Hom.:

Cov.:

AF XY:

0.000311

AC XY:

226

AN XY:

726596

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000689

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000210

Gnomad4 NFE exome

AF:

0.000300

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000519

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000471

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000823

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.00162

Hom.:

Bravo

AF:

0.000325

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 05, 2023	The ALK c.469C>T; p.Pro157Ser variant (rs74774946), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 239842). This variant is found in the non-Finnish European population with an allele frequency of 0.063% (79/125,556 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.031). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2023	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 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 05, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 30, 2018	The p.P157S variant (also known as c.469C>T), located in coding exon 1 of the ALK gene, results from a C to T substitution at nucleotide position 469. The proline at codon 157 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

ALK-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2024

The ALK c.469C>T variant is predicted to result in the amino acid substitution p.Pro157Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.068% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/239842). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.57

M_CAP

Benign

0.084

MetaRNN

Benign

0.0099

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.69

MutationTaster

Benign

0.88

N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.45

REVEL

Benign

0.031

Sift

Uncertain

0.028

Sift4G

Uncertain

0.053

Polyphen

0.0

Vest4

0.15

MVP

0.44

MPC

0.17

ClinPred

0.033

GERP RS

-0.74

Varity_R

0.028

gMVP

0.17

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