2-29193251-C-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004304.5(ALK):​c.4836G>C​(p.Lys1612Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1612Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ALK
NM_004304.5 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 2.90

Publications

6 publications found
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]
CLIP4 (HGNC:26108): (CAP-Gly domain containing linker protein family member 4) Predicted to enable microtubule plus-end binding activity. Predicted to be involved in cytoplasmic microtubule organization. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0328528).
BP6
Variant 2-29193251-C-G is Benign according to our data. Variant chr2-29193251-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 422630. Variant chr2-29193251-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 422630. Variant chr2-29193251-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 422630. Variant chr2-29193251-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 422630. Variant chr2-29193251-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 422630. Variant chr2-29193251-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 422630.
BS2
High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALKNM_004304.5 linkc.4836G>C p.Lys1612Asn missense_variant Exon 29 of 29 ENST00000389048.8 NP_004295.2 Q9UM73B6D4Y2
ALKNM_001353765.2 linkc.1632G>C p.Lys544Asn missense_variant Exon 10 of 10 NP_001340694.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALKENST00000389048.8 linkc.4836G>C p.Lys1612Asn missense_variant Exon 29 of 29 1 NM_004304.5 ENSP00000373700.3 Q9UM73

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000829
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000557
AC:
14
AN:
251280
AF XY:
0.0000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1461864
Hom.:
0
Cov.:
31
AF XY:
0.0000206
AC XY:
15
AN XY:
727232
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.000278
AC:
24
AN:
86244
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1112002
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.479
Heterozygous variant carriers
0
3
5
8
10
13
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152272
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74452
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41554
American (AMR)
AF:
0.00
AC:
0
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5180
South Asian (SAS)
AF:
0.000829
AC:
4
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68018
Other (OTH)
AF:
0.00
AC:
0
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.538
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
1
Bravo
AF:
0.00000378
ExAC
AF:
0.0000906
AC:
11

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Uncertain:1
Nov 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1612 of the ALK protein (p.Lys1612Asn). This variant is present in population databases (rs78174819, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ALK-related conditions. ClinVar contains an entry for this variant (Variation ID: 422630). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1
Oct 27, 2016
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is denoted ALK c.4836G>C at the cDNA level, p.Lys1612Asn (K1612N) at the protein level, and results in the change of a Lysine to an Asparagine (AAG>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ALK Lys1612Asn was not observed at a significant allele frequency in 1000 Genomes. Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. ALK Lys1612Asn occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ALK Lys1612Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Benign:1
Jun 26, 2024
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
AlphaMissense
Benign
0.29
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.032
T;T;.
Eigen
Benign
-0.11
Eigen_PC
Benign
-0.21
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.74
T;T;T
M_CAP
Benign
0.076
D
MetaRNN
Benign
0.033
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.90
.;L;.
PhyloP100
2.9
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-2.0
.;N;.
REVEL
Benign
0.070
Sift
Uncertain
0.016
.;D;.
Sift4G
Uncertain
0.026
.;D;T
Polyphen
0.95
.;P;.
Vest4
0.31, 0.28
MutPred
0.15
.;Loss of ubiquitination at K1612 (P = 0.0014);.;
MVP
0.56
MPC
0.62
ClinPred
0.21
T
GERP RS
2.5
Varity_R
0.23
gMVP
0.44
Mutation Taster
=77/23
polymorphism

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

Other links and lift over

dbSNP: rs78174819; hg19: chr2-29416117; COSMIC: COSV106064235; API