2-29220751-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004304.5(ALK):c.3600G>C(p.Ala1200=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,613,912 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1200A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0023 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 121 hom. )

Consequence

ALK
NM_004304.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.88

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 2-29220751-C-G is Benign according to our data. Variant chr2-29220751-C-G is described in ClinVar as [Benign]. Clinvar id is 239827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-29220751-C-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.88 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5 linkuse as main transcript	c.3600G>C	p.Ala1200=	synonymous_variant	23/29	ENST00000389048.8
ALK	NM_001353765.2 linkuse as main transcript	c.396G>C	p.Ala132=	synonymous_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8 linkuse as main transcript	c.3600G>C	p.Ala1200=	synonymous_variant	23/29	1	NM_004304.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00230

AC:

350

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0590

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00419

AC:

1051

AN:

250662

Hom.:

AF XY:

0.00379

AC XY:

514

AN XY:

135502

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0547

Gnomad SAS exome

AF:

0.000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000619

Gnomad OTH exome

AF:

0.00262

GnomAD4 exome

AF:

0.00224

AC:

3280

AN:

1461638

Hom.:

121

Cov.:

AF XY:

0.00209

AC XY:

1523

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0748

Gnomad4 SAS exome

AF:

0.000545

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.00346

GnomAD4 genome

AF:

0.00230

AC:

350

AN:

152274

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

186

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0591

Gnomad4 SAS

AF:

0.00208

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000261

Hom.:

Bravo

AF:

0.00225

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:9

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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 02, 2020	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 03, 2018	Variant summary: ALK c.3600G>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0039 in 276458 control chromosomes in the gnomAD database, including 31 homozygotes. The observed variant frequency is approximately 9306-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in ALK causing Neuroblastoma, Susceptibility Type 3 phenotype (4.2e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3600G>C in individuals affected with Neuroblastoma, Susceptibility Type 3 and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 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

-0.79

Cadd

Benign

0.0020

Dann

Benign

0.63

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