rs1168592296

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3PM5PP3_StrongPP5

The NM_000080.4(CHRNE):c.1052C>T(p.Pro351Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000847 in 1,534,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV004028917: HEK293 cells expressing the epsilon-subunit with the variant lack the ability to bind alpha-Bungarotoxin, and that the protein fails to incorporate into the surface AChR complex (Croxen_2001). PMID:11408331" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P351S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000087 ( 0 hom. )

Consequence

CHRNE
NM_000080.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 5.25

Publications

2 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: Pathogenic. The variant received 11 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV004028917: HEK293 cells expressing the epsilon-subunit with the variant lack the ability to bind alpha-Bungarotoxin, and that the protein fails to incorporate into the surface AChR complex (Croxen_2001). PMID: 11408331; SCV004109217: "In expression studies, the p.Pro351Leu substitution was reported to severely reduce surface expression of acetylcholine receptor (Croxen et al. 2001. PubMed ID: 11408331)."; SCV005904076: "Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 11408331)."

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-4899365-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2577839.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 17-4899365-G-A is Pathogenic according to our data. Variant chr17-4899365-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465851.

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.1052C>T	p.Pro351Leu	missense	Exon 10 of 12	NP_000071.1	Q04844
	C17orf107	NM_001145536.2	MANE Select	c.-398G>A		upstream_gene	N/A	NP_001139008.1	Q6ZR85

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRNE	ENST00000649488.2	MANE Select	c.1052C>T	p.Pro351Leu	missense	Exon 10 of 12	ENSP00000497829.1	Q04844
CHRNE	ENST00000649830.1		c.119C>T	p.Pro40Leu	missense	Exon 10 of 11	ENSP00000496907.1	A0A3B3IRM1
CHRNE	ENST00000572438.1	TSL:5	n.738C>T		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000868

AC:

AN:

1382156

Hom.:

Cov.:

AF XY:

0.0000132

AC XY:

AN XY:

682604

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31266

American (AMR)

AF:

0.00

AC:

AN:

33680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24360

East Asian (EAS)

AF:

0.00

AC:

AN:

35962

South Asian (SAS)

AF:

0.00

AC:

AN:

78956

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37868

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4758

European-Non Finnish (NFE)

AF:

0.0000111

AC:

AN:

1077852

Other (OTH)

AF:

0.00

AC:

AN:

57454

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

CHRNE-related disorder (1)

Congenital myasthenic syndrome (1)

Congenital myasthenic syndrome 4A (1)

Congenital myasthenic syndrome 4C (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

0.81

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

4.2

PhyloP100

5.3

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-8.6

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.78

MutPred

0.88

Loss of loop (P = 0.0374)

MVP

0.95

MPC

0.70

ClinPred

1.0

GERP RS

4.9

PromoterAI

-0.033

Neutral

(source)

Varity_R

0.86

gMVP

0.81

Mutation Taster

=20/80

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over