rs140023380

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_000080.4(CHRNE):c.901G>A(p.Val301Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000579 in 1,613,810 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V301L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00060 ( 1 hom. )

Consequence

CHRNE
NM_000080.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:4

Conservation

PhyloP100: 2.17

Publications

3 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 links:

C17orf107 (HGNC:37238): (chromosome 17 open reading frame 107)

C17orf107 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000080.4

BP4

Computational evidence support a benign effect (MetaRNN=0.08342728).

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.901G>A	p.Val301Met	missense	Exon 8 of 12	NP_000071.1	Q04844
	C17orf107	NM_001145536.2	MANE Select	c.*276C>T		3_prime_UTR	Exon 3 of 3	NP_001139008.1	Q6ZR85

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRNE	ENST00000649488.2	MANE Select	c.901G>A	p.Val301Met	missense	Exon 8 of 12	ENSP00000497829.1	Q04844
C17orf107	ENST00000381365.4	TSL:2 MANE Select	c.*276C>T		3_prime_UTR	Exon 3 of 3	ENSP00000370770.3	Q6ZR85
CHRNE	ENST00000649830.1		c.-33G>A		5_prime_UTR_premature_start_codon_gain	Exon 8 of 11	ENSP00000496907.1	A0A3B3IRM1

Frequencies

GnomAD3 genomes

AF:

0.000420

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000558

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000705

AC:

175

AN:

248052

AF XY:

0.000728

show subpopulations

Gnomad AFR exome

AF:

0.000435

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00400

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000325

Gnomad NFE exome

AF:

0.000893

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000596

AC:

871

AN:

1461574

Hom.:

Cov.:

AF XY:

0.000602

AC XY:

438

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33472

American (AMR)

AF:

0.000291

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00379

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000638

AC:

709

AN:

1111830

Other (OTH)

AF:

0.000398

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

106

160

213

266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000420

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.000314

AC:

AN:

41464

American (AMR)

AF:

0.000131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000558

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000733

Hom.:

Bravo

AF:

0.000601

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000667

AC:

EpiCase

AF:

0.00120

EpiControl

AF:

0.000949

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital myasthenic syndrome (2)

CHRNE-related disorder (1)

Congenital myasthenic syndrome 4A (1)

not provided (1)

not specified (1)

Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.083

MetaSVM

Uncertain

0.56

MutationAssessor

Pathogenic

3.1

PhyloP100

2.2

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.68

Sift

Uncertain

0.024

Sift4G

Uncertain

0.0020

Polyphen

0.95

Vest4

0.43

MVP

0.90

MPC

0.34

ClinPred

0.14

GERP RS

5.0

Varity_R

0.71

gMVP

0.71

Mutation Taster

=93/7

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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