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rs565743321

chr2-29297016-G-Achr2-29297016-G-Cchr2-29297016-G-T

Variant summary

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

The NM_004304.5(ALK):c.1689C>T(p.Asn563=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000516 in 1,614,160 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00054 ( 7 hom. )

Consequence

ALK
NM_004304.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.914
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
?
    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=-0.71).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-29297016-G-A is Benign according to our data. Variant chr2-29297016-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 412925.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=-0.914 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000309 (47/152296) while in subpopulation SAS AF= 0.0083 (40/4822). AF 95% confidence interval is 0.00626. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 33. 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 48 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ALKNM_004304.5 linkuse as main transcriptc.1689C>T p.Asn563= synonymous_variant 9/29 ENST00000389048.8
ALKXR_001738688.3 linkuse as main transcriptn.2616C>T non_coding_transcript_exon_variant 9/18

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ALKENST00000389048.8 linkuse as main transcriptc.1689C>T p.Asn563= synonymous_variant 9/291 NM_004304.5 P1
ALKENST00000618119.4 linkuse as main transcriptc.558C>T p.Asn186= synonymous_variant 8/285
ALKENST00000498037.1 linkuse as main transcriptn.244C>T non_coding_transcript_exon_variant 3/54

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000315
AC:
48
AN:
152178
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00850
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00110
AC:
276
AN:
251020
Hom.:
2
AF XY:
0.00145
AC XY:
197
AN XY:
135642
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000218
Gnomad SAS exome
AF:
0.00852
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000441
Gnomad OTH exome
AF:
0.000490
GnomAD4 exome
AF:
0.000538
AC:
786
AN:
1461864
Hom.:
7
Cov.:
32
AF XY:
0.000770
AC XY:
560
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00787
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000459
Gnomad4 OTH exome
AF:
0.000745
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000309
AC:
47
AN:
152296
Hom.:
0
Cov.:
33
AF XY:
0.000416
AC XY:
31
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00830
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000246
Hom.:
0
Bravo
AF:
0.000144
Asia WGS
AF:
0.00318
AC:
11
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 15, 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. -
Benign, criteria provided, single submittercurationSema4, Sema4Feb 24, 2020- -
Neuroblastoma, susceptibility to, 3 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2022ALK: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.71
Cadd
Benign
1.6
Dann
Benign
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs565743321; hg19: chr2-29519882; COSMIC: COSV66578866; API