rs33978919

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000080.4(CHRNE):c.1293C>T(p.Ala431Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,609,810 control chromosomes in the GnomAD database, including 18,126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2968 hom., cov: 33)

Exomes 𝑓: 0.14 ( 15158 hom. )

Consequence

CHRNE
NM_000080.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -2.07

Publications

11 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

CHRNE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 17-4899034-G-A is Benign according to our data. Variant chr17-4899034-G-A is described in ClinVar as Benign. ClinVar VariationId is 128762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.07 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNE	NM_000080.4 link	c.1293C>T	p.Ala431Ala	synonymous_variant	Exon 11 of 12	ENST00000649488.2	NP_000071.1
CHRNE	XM_017024115.2 link	c.1257C>T	p.Ala419Ala	synonymous_variant	Exon 12 of 13		XP_016879604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CHRNE	ENST00000649488.2 link	c.1293C>T	p.Ala431Ala	synonymous_variant	Exon 11 of 12		NM_000080.4	ENSP00000497829.1
CHRNE	ENST00000649830.1 link	c.360C>T	p.Ala120Ala	synonymous_variant	Exon 11 of 11			ENSP00000496907.1
CHRNE	ENST00000572438.1 link	n.979C>T		non_coding_transcript_exon_variant	Exon 6 of 7	5
CHRNE	ENST00000652550.1 link	n.1023C>T		non_coding_transcript_exon_variant	Exon 3 of 4

Frequencies

GnomAD3 genomes

AF:

0.182

AC:

27646

AN:

152024

Hom.:

2967

Cov.:

show subpopulations

Gnomad AFR

AF:

0.295

Gnomad AMI

AF:

0.150

Gnomad AMR

AF:

0.181

Gnomad ASJ

AF:

0.157

Gnomad EAS

AF:

0.0595

Gnomad SAS

AF:

0.149

Gnomad FIN

AF:

0.115

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.137

Gnomad OTH

AF:

0.189

GnomAD2 exomes

AF:

0.146

AC:

35202

AN:

240626

AF XY:

0.144

show subpopulations

Gnomad AFR exome

AF:

0.301

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.147

Gnomad EAS exome

AF:

0.0557

Gnomad FIN exome

AF:

0.124

Gnomad NFE exome

AF:

0.138

Gnomad OTH exome

AF:

0.153

GnomAD4 exome

AF:

0.140

AC:

204253

AN:

1457666

Hom.:

15158

Cov.:

AF XY:

0.140

AC XY:

101479

AN XY:

724782

show subpopulations

African (AFR)

AF:

0.300

AC:

10049

AN:

33462

American (AMR)

AF:

0.165

AC:

7298

AN:

44292

Ashkenazi Jewish (ASJ)

AF:

0.147

AC:

3834

AN:

26038

East Asian (EAS)

AF:

0.0921

AC:

3648

AN:

39622

South Asian (SAS)

AF:

0.150

AC:

12787

AN:

85484

European-Finnish (FIN)

AF:

0.125

AC:

6510

AN:

51892

Middle Eastern (MID)

AF:

0.208

AC:

1198

AN:

5764

European-Non Finnish (NFE)

AF:

0.135

AC:

150029

AN:

1110876

Other (OTH)

AF:

0.148

AC:

8900

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

11526

23052

34578

46104

57630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5510

11020

16530

22040

27550

<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:

0.182

AC:

27679

AN:

152144

Hom.:

2968

Cov.:

AF XY:

0.179

AC XY:

13325

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.295

AC:

12244

AN:

41482

American (AMR)

AF:

0.181

AC:

2764

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

544

AN:

3470

East Asian (EAS)

AF:

0.0598

AC:

309

AN:

5168

South Asian (SAS)

AF:

0.149

AC:

717

AN:

4820

European-Finnish (FIN)

AF:

0.115

AC:

1215

AN:

10610

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.137

AC:

9305

AN:

67988

Other (OTH)

AF:

0.186

AC:

393

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1145

2291

3436

4582

5727

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

274

548

822

1096

1370

<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:

0.156

Hom.:

939

Bravo

AF:

0.192

Asia WGS

AF:

0.130

AC:

452

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jun 23, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 07, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Congenital myasthenic syndrome 4A

Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Congenital myasthenic syndrome

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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.

Congenital myasthenic syndrome 4C

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Congenital myasthenic syndrome 4B

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: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

-0.75

CADD

Benign

5.5

(source)

DANN

Benign

0.93

PhyloP100

-2.1

PromoterAI

-0.0059

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over