NM_000080.4:c.1402G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000080.4(CHRNE):c.1402G>C(p.Val468Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00795 in 1,603,472 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V468M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0056 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0082 ( 90 hom. )

Consequence

CHRNE
NM_000080.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.492

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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
congenital myasthenic syndrome 4B
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0081155).

BP6

Variant 17-4898816-C-G is Benign according to our data. Variant chr17-4898816-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00558 (849/152282) while in subpopulation SAS AF = 0.0168 (81/4826). AF 95% confidence interval is 0.0138. There are 10 homozygotes in GnomAd4. There are 441 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000080.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	NM_000080.4	MANE Select	c.1402G>C	p.Val468Leu	missense	Exon 12 of 12	NP_000071.1	Q04844

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRNE	ENST00000649488.2	MANE Select	c.1402G>C	p.Val468Leu	missense	Exon 12 of 12	ENSP00000497829.1	Q04844
CHRNE	ENST00000649830.1		c.*38G>C		3_prime_UTR	Exon 11 of 11	ENSP00000496907.1	A0A3B3IRM1
CHRNE	ENST00000572438.1	TSL:5	n.1088G>C		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes

AF:

0.00561

AC:

853

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00752

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0168

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00785

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00753

AC:

1708

AN:

226956

AF XY:

0.00863

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00401

Gnomad ASJ exome

AF:

0.0139

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000567

Gnomad NFE exome

AF:

0.00810

Gnomad OTH exome

AF:

0.00697

GnomAD4 exome

AF:

0.00820

AC:

11893

AN:

1451190

Hom.:

Cov.:

AF XY:

0.00866

AC XY:

6243

AN XY:

720800

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33388

American (AMR)

AF:

0.00420

AC:

178

AN:

42430

Ashkenazi Jewish (ASJ)

AF:

0.0137

AC:

355

AN:

25844

East Asian (EAS)

AF:

0.00

AC:

AN:

39356

South Asian (SAS)

AF:

0.0202

AC:

1707

AN:

84318

European-Finnish (FIN)

AF:

0.000899

AC:

AN:

52304

Middle Eastern (MID)

AF:

0.0144

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00808

AC:

8956

AN:

1107734

Other (OTH)

AF:

0.00886

AC:

532

AN:

60062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

779

1558

2337

3116

3895

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

336

672

1008

1344

1680

<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:

0.00558

AC:

849

AN:

152282

Hom.:

Cov.:

AF XY:

0.00592

AC XY:

441

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

41570

American (AMR)

AF:

0.00751

AC:

115

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.0168

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00782

AC:

532

AN:

68028

Other (OTH)

AF:

0.00664

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

137

183

229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00470

Hom.:

Bravo

AF:

0.00574

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00687

AC:

ExAC

AF:

0.00716

AC:

867

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Congenital myasthenic syndrome (2)

Congenital myasthenic syndrome 4A (2)

Congenital myasthenic syndrome 4C;C4225369:Congenital myasthenic syndrome 4B;C4225413:Congenital myasthenic syndrome 4A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.12

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0081

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.0

PhyloP100

-0.49

PrimateAI

Benign

0.44

PROVEAN

Benign

0.040

REVEL

Benign

0.19

Sift

Benign

0.44

Sift4G

Benign

0.78

Polyphen

0.0060

Vest4

0.026

MutPred

0.52

Loss of sheet (P = 0.0457)

MVP

0.74

MPC

0.17

ClinPred

0.0047

GERP RS

0.89

Varity_R

0.084

gMVP

0.51

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over