17-4899468-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000080.4(CHRNE):​c.1032C>A​(p.His344Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,435,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). 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. H344D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CHRNE
NM_000080.4 missense, splice_region

Scores

1
1
17
Splicing: ADA: 0.00003026
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.767

Publications

0 publications found
Variant links:
Genes affected
C17orf107 (HGNC:37238): (chromosome 17 open reading frame 107)
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: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.21193743).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHRNENM_000080.4 linkc.1032C>A p.His344Gln missense_variant, splice_region_variant Exon 9 of 12 ENST00000649488.2 NP_000071.1 Q04844
C17orf107NM_001145536.2 linkc.-295G>T upstream_gene_variant ENST00000381365.4 NP_001139008.1 Q6ZR85

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHRNEENST00000649488.2 linkc.1032C>A p.His344Gln missense_variant, splice_region_variant Exon 9 of 12 NM_000080.4 ENSP00000497829.1 Q04844
C17orf107ENST00000381365.4 linkc.-295G>T upstream_gene_variant 2 NM_001145536.2 ENSP00000370770.3 Q6ZR85

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.96e-7
AC:
1
AN:
1435752
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
711656
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33186
American (AMR)
AF:
0.00
AC:
0
AN:
40542
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38770
South Asian (SAS)
AF:
0.00
AC:
0
AN:
82204
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49964
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5400
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1100796
Other (OTH)
AF:
0.0000168
AC:
1
AN:
59424
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
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
Cov.:
33
Alfa
AF:
0.00
Hom.:
0

ClinVar

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

Submissions by phenotype

Congenital myasthenic syndrome 4A Uncertain:1
Nov 23, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 344 of the CHRNE protein (p.His344Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHRNE-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.097
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
3.5
DANN
Benign
0.75
DEOGEN2
Benign
0.13
T;T;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.24
N
LIST_S2
Benign
0.40
.;T;T
M_CAP
Pathogenic
0.42
D
MetaRNN
Benign
0.21
T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
-0.38
N;N;.
PhyloP100
-0.77
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
0.57
N;.;.
REVEL
Benign
0.19
Sift
Benign
0.93
T;.;.
Sift4G
Benign
0.52
T;.;.
Polyphen
0.050
B;B;.
Vest4
0.16
MutPred
0.46
Loss of methylation at R341 (P = 0.0481);Loss of methylation at R341 (P = 0.0481);.;
MVP
0.80
MPC
0.18
ClinPred
0.11
T
GERP RS
-1.2
PromoterAI
-0.35
Neutral
Varity_R
0.11
gMVP
0.45
Mutation Taster
=75/25
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000030
dbscSNV1_RF
Benign
0.012
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: rs144047383; hg19: chr17-4802763; API