dbSNP rs192195094: CHRNE:p.Pro359Leu (chr17-4899341-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000080.4(CHRNE):c.1076C>T(p.Pro359Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000511 in 1,547,386 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P359S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0026 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

CHRNE
NM_000080.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.30

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 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: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 25 uncertain in NM_000080.4

BP4

Computational evidence support a benign effect (MetaRNN=0.008722782).

BP6

Variant 17-4899341-G-A is Benign according to our data. Variant chr17-4899341-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 585672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00259 (394/152214) while in subpopulation AFR AF = 0.00878 (365/41554). AF 95% confidence interval is 0.00804. There are 3 homozygotes in GnomAd4. There are 173 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 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.1076C>T	p.Pro359Leu	missense	Exon 10 of 12	NP_000071.1	Q04844
	C17orf107	NM_001145536.2	MANE Select	c.-422G>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.1076C>T	p.Pro359Leu	missense	Exon 10 of 12	ENSP00000497829.1	Q04844
CHRNE	ENST00000649830.1		c.143C>T	p.Pro48Leu	missense	Exon 10 of 11	ENSP00000496907.1	A0A3B3IRM1
CHRNE	ENST00000572438.1	TSL:5	n.762C>T		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes

AF:

0.00260

AC:

395

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00881

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000645

AC:

AN:

145708

AF XY:

0.000556

show subpopulations

Gnomad AFR exome

AF:

0.00999

Gnomad AMR exome

AF:

0.000461

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000856

Gnomad OTH exome

AF:

0.000238

GnomAD4 exome

AF:

0.000284

AC:

396

AN:

1395172

Hom.:

Cov.:

AF XY:

0.000258

AC XY:

178

AN XY:

690180

show subpopulations

African (AFR)

AF:

0.00887

AC:

281

AN:

31664

American (AMR)

AF:

0.000449

AC:

AN:

35616

Ashkenazi Jewish (ASJ)

AF:

0.0000400

AC:

AN:

25016

East Asian (EAS)

AF:

0.00

AC:

AN:

36430

South Asian (SAS)

AF:

0.0000993

AC:

AN:

80588

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37850

Middle Eastern (MID)

AF:

0.00159

AC:

AN:

5042

European-Non Finnish (NFE)

AF:

0.0000452

AC:

AN:

1084922

Other (OTH)

AF:

0.000569

AC:

AN:

58044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00259

AC:

394

AN:

152214

Hom.:

Cov.:

AF XY:

0.00232

AC XY:

173

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00878

AC:

365

AN:

41554

American (AMR)

AF:

0.000915

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67986

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000248

Hom.:

Bravo

AF:

0.00294

ExAC

AF:

0.000742

AC:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

CHRNE-related disorder (1)

Congenital myasthenic syndrome (1)

Congenital myasthenic syndrome 4A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0087

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.1

PhyloP100

3.3

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.38

Sift

Benign

0.15

Sift4G

Benign

0.25

Polyphen

0.97

Vest4

0.24

MVP

0.93

MPC

0.17

ClinPred

0.050

GERP RS

4.9

PromoterAI

-0.025

Neutral

(source)

Varity_R

0.099

gMVP

0.66

Mutation Taster

=97/3

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