2-29223365-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000389048.8(ALK):​c.3336G>A​(p.Pro1112=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00062 in 1,614,136 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1112P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00064 ( 13 hom. )

Consequence

ALK
ENST00000389048.8 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -6.08
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
Variant 2-29223365-C-T is Benign according to our data. Variant chr2-29223365-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 335695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-29223365-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-6.07 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000381 (58/152294) while in subpopulation EAS AF= 0.00869 (45/5180). AF 95% confidence interval is 0.00667. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ALKNM_004304.5 linkuse as main transcriptc.3336G>A p.Pro1112= synonymous_variant 20/29 ENST00000389048.8 NP_004295.2
ALKNM_001353765.2 linkuse as main transcriptc.132G>A p.Pro44= synonymous_variant 1/10 NP_001340694.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ALKENST00000389048.8 linkuse as main transcriptc.3336G>A p.Pro1112= synonymous_variant 20/291 NM_004304.5 ENSP00000373700 P1

Frequencies

GnomAD3 genomes
AF:
0.000381
AC:
58
AN:
152176
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00867
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000482
AC:
121
AN:
251196
Hom.:
0
AF XY:
0.000449
AC XY:
61
AN XY:
135766
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00593
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000644
AC:
942
AN:
1461842
Hom.:
13
Cov.:
34
AF XY:
0.000613
AC XY:
446
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0226
Gnomad4 SAS exome
AF:
0.000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.000381
AC:
58
AN:
152294
Hom.:
0
Cov.:
33
AF XY:
0.000443
AC XY:
33
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00869
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000168
Hom.:
0
Bravo
AF:
0.000359
Asia WGS
AF:
0.00404
AC:
14
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxDec 09, 2016This 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. -
ALK-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesOct 02, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 16, 2017This 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
-0.80
CADD
Benign
0.014
DANN
Benign
0.71

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.

Other links and lift over

dbSNP: rs146074150; hg19: chr2-29446231; COSMIC: COSV66582490; API