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rs149853746

chr2-29239767-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.2268C>T(p.Gly756=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00057 in 1,614,014 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00034 ( 3 hom. )

Consequence

ALK
NM_004304.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.47
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 -19 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.28).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-29239767-G-A is Benign according to our data. Variant chr2-29239767-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 412906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-1.47 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0028 (426/152282) while in subpopulation AFR AF= 0.00973 (404/41542). AF 95% confidence interval is 0.00894. There are 2 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 426 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ALKNM_004304.5 linkuse as main transcriptc.2268C>T p.Gly756= synonymous_variant 13/29 ENST00000389048.8
ALKXR_001738688.3 linkuse as main transcriptn.3195C>T non_coding_transcript_exon_variant 13/18

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ALKENST00000389048.8 linkuse as main transcriptc.2268C>T p.Gly756= synonymous_variant 13/291 NM_004304.5 P1
ALKENST00000618119.4 linkuse as main transcriptc.1137C>T p.Gly379= synonymous_variant 12/285

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00280
AC:
426
AN:
152164
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00975
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000982
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000717
AC:
180
AN:
251162
Hom.:
0
AF XY:
0.000552
AC XY:
75
AN XY:
135760
show subpopulations
Gnomad AFR exome
AF:
0.00911
Gnomad AMR exome
AF:
0.000521
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000704
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000338
AC:
494
AN:
1461732
Hom.:
3
Cov.:
32
AF XY:
0.000309
AC XY:
225
AN XY:
727174
show subpopulations
Gnomad4 AFR exome
AF:
0.0114
Gnomad4 AMR exome
AF:
0.000559
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000279
Gnomad4 OTH exome
AF:
0.000828
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00280
AC:
426
AN:
152282
Hom.:
2
Cov.:
32
AF XY:
0.00251
AC XY:
187
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.00973
Gnomad4 AMR
AF:
0.000980
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00159
Hom.:
0
Bravo
AF:
0.00344
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000237

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submittercurationSema4, Sema4Nov 08, 2020- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 12, 2022This 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. -
not specified Benign:1
Benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of ChicagoJul 28, 2022- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxJan 23, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.28
Cadd
Benign
8.2
Dann
Benign
0.65

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: rs149853746; hg19: chr2-29462633; COSMIC: COSV66566547; API