ENST00000574453.5:n.*4369C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The ENST00000574453.5(MINK1):​n.*4369C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 141,436 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 28)
Exomes 𝑓: 0.0052 ( 0 hom. )

Consequence

MINK1
ENST00000574453.5 non_coding_transcript_exon

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.363

Publications

0 publications found
Variant links:
Genes affected
MINK1 (HGNC:17565): (misshapen like kinase 1) This gene encodes a serine/threonine kinase belonging to the germinal center kinase (GCK) family. The protein is structurally similar to the kinases that are related to NIK and may belong to a distinct subfamily of NIK-related kinases within the GCK family. Studies of the mouse homolog indicate an up-regulation of expression in the course of postnatal mouse cerebral development and activation of the cJun N-terminal kinase (JNK) and the p38 pathways. [provided by RefSeq, Mar 2016]
CHRNE (HGNC:1966): (cholinergic receptor nicotinic epsilon subunit) Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome. [provided by RefSeq, Sep 2009]
CHRNE Gene-Disease associations (from GenCC):
  • congenital myasthenic syndrome
    Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina
  • congenital myasthenic syndrome 4A
    Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
  • congenital myasthenic syndrome 4B
    Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
  • congenital myasthenic syndrome 4C
    Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
  • postsynaptic congenital myasthenic syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BP6
Variant 17-4897988-C-T is Benign according to our data. Variant chr17-4897988-C-T is described in ClinVar as [Benign]. Clinvar id is 892125.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 at 161 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MINK1NM_153827.5 linkc.*701C>T 3_prime_UTR_variant Exon 32 of 32 ENST00000355280.11 NP_722549.2 Q8N4C8-1
CHRNENM_000080.4 linkc.*748G>A 3_prime_UTR_variant Exon 12 of 12 ENST00000649488.2 NP_000071.1 Q04844

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MINK1ENST00000355280.11 linkc.*701C>T 3_prime_UTR_variant Exon 32 of 32 1 NM_153827.5 ENSP00000347427.6 Q8N4C8-1
CHRNEENST00000649488.2 linkc.*748G>A 3_prime_UTR_variant Exon 12 of 12 NM_000080.4 ENSP00000497829.1 Q04844

Frequencies

GnomAD3 genomes
AF:
0.00114
AC:
161
AN:
140918
Hom.:
1
Cov.:
28
show subpopulations
Gnomad AFR
AF:
0.00120
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000787
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00145
Gnomad SAS
AF:
0.000729
Gnomad FIN
AF:
0.000111
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00140
Gnomad OTH
AF:
0.00155
GnomAD4 exome
AF:
0.00518
AC:
2
AN:
386
Hom.:
0
Cov.:
0
AF XY:
0.00581
AC XY:
1
AN XY:
172
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AC:
0
AN:
0
American (AMR)
AF:
0.00
AC:
0
AN:
46
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
4
East Asian (EAS)
AF:
0.00
AC:
0
AN:
2
South Asian (SAS)
AF:
0.00
AC:
0
AN:
30
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
26
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
2
European-Non Finnish (NFE)
AF:
0.00763
AC:
2
AN:
262
Other (OTH)
AF:
0.00
AC:
0
AN:
14
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.275
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00114
AC:
161
AN:
141050
Hom.:
1
Cov.:
28
AF XY:
0.00110
AC XY:
75
AN XY:
68474
show subpopulations
African (AFR)
AF:
0.00120
AC:
48
AN:
39972
American (AMR)
AF:
0.000786
AC:
11
AN:
13992
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3256
East Asian (EAS)
AF:
0.00146
AC:
7
AN:
4810
South Asian (SAS)
AF:
0.000727
AC:
3
AN:
4126
European-Finnish (FIN)
AF:
0.000111
AC:
1
AN:
9022
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
284
European-Non Finnish (NFE)
AF:
0.00140
AC:
88
AN:
62798
Other (OTH)
AF:
0.00154
AC:
3
AN:
1954
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.561
Heterozygous variant carriers
0
7
13
20
26
33
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
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:
0.000430
Hom.:
2

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Congenital myasthenic syndrome Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.89
CADD
Benign
1.3
DANN
Benign
0.49
PhyloP100
-0.36
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.2
Mutation Taster
=100/0
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs536398300; hg19: chr17-4801283; API