chr17-4898731-G-A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000080.4(CHRNE):​c.*5C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,608,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

CHRNE
NM_000080.4 3_prime_UTR

Scores

2

Clinical Significance

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

Conservation

PhyloP100: -1.01

Publications

0 publications found
Variant links:
Genes affected
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: Likely_benign. The variant received -4 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHRNENM_000080.4 linkc.*5C>T 3_prime_UTR_variant Exon 12 of 12 ENST00000649488.2 NP_000071.1 Q04844
CHRNEXM_017024115.2 linkc.*5C>T 3_prime_UTR_variant Exon 13 of 13 XP_016879604.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHRNEENST00000649488.2 linkc.*5C>T 3_prime_UTR_variant Exon 12 of 12 NM_000080.4 ENSP00000497829.1 Q04844
CHRNEENST00000572438.1 linkn.1173C>T non_coding_transcript_exon_variant Exon 7 of 7 5
CHRNEENST00000652550.1 linkn.1213C>T non_coding_transcript_exon_variant Exon 4 of 4
CHRNEENST00000649830.1 linkc.*123C>T 3_prime_UTR_variant Exon 11 of 11 ENSP00000496907.1 A0A3B3IRM1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152168
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000415
AC:
10
AN:
240964
AF XY:
0.0000460
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000298
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000826
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000378
AC:
55
AN:
1456700
Hom.:
0
Cov.:
34
AF XY:
0.0000428
AC XY:
31
AN XY:
724118
show subpopulations
African (AFR)
AF:
0.000149
AC:
5
AN:
33454
American (AMR)
AF:
0.0000228
AC:
1
AN:
43904
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25922
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39566
South Asian (SAS)
AF:
0.0000117
AC:
1
AN:
85134
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52752
Middle Eastern (MID)
AF:
0.000174
AC:
1
AN:
5760
European-Non Finnish (NFE)
AF:
0.0000369
AC:
41
AN:
1110000
Other (OTH)
AF:
0.0000997
AC:
6
AN:
60208
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.476
Heterozygous variant carriers
0
3
6
10
13
16
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:
0.0000197
AC:
3
AN:
152286
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74460
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41564
American (AMR)
AF:
0.00
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68006
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
1
1
2
2
3
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:
0.000128
Hom.:
0
Bravo
AF:
0.0000416

ClinVar

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

Submissions by phenotype

Congenital myasthenic syndrome Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1
-
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.83
CADD
Benign
0.18
DANN
Benign
0.65
PhyloP100
-1.0

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: rs747566295; hg19: chr17-4802026; API