dbSNP rs193919341: CHRNE:p.Trp75Arg (chr17-4902461-A-G) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000080.4(CHRNE):c.223T>C(p.Trp75Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CHRNE
NM_000080.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.69

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: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a topological_domain Extracellular (size 218) in uniprot entity ACHE_HUMAN there are 29 pathogenic changes around while only 6 benign (83%) in NM_000080.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 17-4902461-A-G is Pathogenic according to our data. Variant chr17-4902461-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 40201.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNE	NM_000080.4 link	c.223T>C	p.Trp75Arg	missense_variant	Exon 3 of 12	ENST00000649488.2	NP_000071.1	Q04844
C17orf107	NM_001145536.2 link	c.*1928A>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000381365.4	NP_001139008.1	Q6ZR85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHRNE	ENST00000649488.2 link	c.223T>C	p.Trp75Arg	missense_variant	Exon 3 of 12		NM_000080.4	ENSP00000497829.1	Q04844
C17orf107	ENST00000381365.4 link	c.*1928A>G		3_prime_UTR_variant	Exon 3 of 3	2	NM_001145536.2	ENSP00000370770.3	Q6ZR85
CHRNE	ENST00000575637.1 link	n.44T>C		non_coding_transcript_exon_variant	Exon 2 of 6	3
CHRNE	ENST00000649830.1 link	c.-711T>C		5_prime_UTR_variant	Exon 3 of 11			ENSP00000496907.1	A0A3B3IRM1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 4B

Pathogenic:1

Jul 31, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

D;D

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

.;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

8.7

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-10

D;.

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.0050

D;.

Polyphen

1.0

D;D

Vest4

0.98

MutPred

0.88

Gain of disorder (P = 0.037);Gain of disorder (P = 0.037);

MVP

0.93

MPC

0.94

ClinPred

1.0

GERP RS

4.9

Varity_R

0.95

gMVP

0.94

Mutation Taster

=16/84

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over