rs56165377

Positions:

chr2-29320833-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004304.5(ALK):c.1464C>T(p.Gly488=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.009 in 1,614,186 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0093 ( 95 hom. )

Consequence

ALK
NM_004304.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 2-29320833-G-A is Benign according to our data. Variant chr2-29320833-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-29320833-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=2.37 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00606 (923/152320) while in subpopulation AMR AF= 0.00947 (145/15306). AF 95% confidence interval is 0.00833. There are 2 homozygotes in gnomad4. There are 432 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 923 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ALK	NM_004304.5 linkuse as main transcript	c.1464C>T	p.Gly488=	synonymous_variant	7/29	ENST00000389048.8	NP_004295.2
LOC101929386	XR_007086263.1 linkuse as main transcript	n.376+860G>A		intron_variant, non_coding_transcript_variant
ALK	XR_001738688.3 linkuse as main transcript	n.2391C>T		non_coding_transcript_exon_variant	7/18
LOC101929386	XR_939920.3 linkuse as main transcript	n.89-646G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ALK	ENST00000389048.8 linkuse as main transcript	c.1464C>T	p.Gly488=	synonymous_variant	7/29	1	NM_004304.5	ENSP00000373700	P1
	ENST00000655343.1 linkuse as main transcript	n.220+860G>A		intron_variant, non_coding_transcript_variant
ALK	ENST00000618119.4 linkuse as main transcript	c.333C>T	p.Gly111=	synonymous_variant	6/28	5		ENSP00000482733

Frequencies

GnomAD3 genomes

AF:

0.00606

AC:

923

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00186

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00949

Gnomad ASJ

AF:

0.00606

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00424

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00892

Gnomad OTH

AF:

0.00573

GnomAD3 exomes

AF:

0.00598

AC:

1503

AN:

251410

Hom.:

AF XY:

0.00599

AC XY:

814

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00561

Gnomad ASJ exome

AF:

0.00506

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00499

Gnomad NFE exome

AF:

0.00943

Gnomad OTH exome

AF:

0.00929

GnomAD4 exome

AF:

0.00930

AC:

13600

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00907

AC XY:

6599

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00137

Gnomad4 AMR exome

AF:

0.00610

Gnomad4 ASJ exome

AF:

0.00421

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00505

Gnomad4 NFE exome

AF:

0.0111

Gnomad4 OTH exome

AF:

0.00881

GnomAD4 genome

AF:

0.00606

AC:

923

AN:

152320

Hom.:

Cov.:

AF XY:

0.00580

AC XY:

432

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00185

Gnomad4 AMR

AF:

0.00947

Gnomad4 ASJ

AF:

0.00606

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00424

Gnomad4 NFE

AF:

0.00892

Gnomad4 OTH

AF:

0.00567

Alfa

AF:

0.00730

Hom.:

Bravo

AF:

0.00654

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0101

EpiControl

AF:

0.0114

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2016	Variant summary: The ALK c.1464C>T (p.Gly488Gly) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 681/121400 control chromosomes (5 homozygotes) at a frequency of 0.0056096, which is approximately 13463 times the estimated maximal expected allele frequency of a pathogenic ALK variant (0.0000004), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ALK: BP4, BS2; ENSG00000286963: BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 06, 2017	This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.73

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