17-7445306-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000747.3(CHRNB1):c.95A>G(p.Glu32Gly) variant causes a missense change. The variant allele was found at a frequency of 0.319 in 1,612,188 control chromosomes in the GnomAD database, including 91,748 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 6030 hom., cov: 32)

Exomes 𝑓: 0.33 ( 85718 hom. )

Consequence

CHRNB1
NM_000747.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 6.06

Publications

27 publications found

Variant links:

Genes affected

CHRNB1 (HGNC:1961): (cholinergic receptor nicotinic beta 1 subunit) The muscle acetylcholine receptor is composed of five subunits: two alpha subunits and one beta, one gamma, and one delta subunit. This gene encodes the beta subunit of the acetylcholine receptor. The acetylcholine receptor changes conformation upon acetylcholine binding leading to the opening of an ion-conducting channel across the plasma membrane. Mutations in this gene are associated with slow-channel congenital myasthenic syndrome. [provided by RefSeq, Jul 2008]

CHRNB1 Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 2C
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
congenital myasthenic syndrome 1A
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
congenital myasthenic syndrome 2A
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CHRNB1 links:

ENSG00000272884 (HGNC:):

ENSG00000272884 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=0.0031630695).

BP6

Variant 17-7445306-A-G is Benign according to our data. Variant chr17-7445306-A-G is described in ClinVar as Benign. ClinVar VariationId is 128754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000747.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB1	NM_000747.3	MANE Select	c.95A>G	p.Glu32Gly	missense	Exon 2 of 11	NP_000738.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHRNB1	ENST00000306071.7	TSL:1 MANE Select	c.95A>G	p.Glu32Gly	missense	Exon 2 of 11	ENSP00000304290.2
ENSG00000272884	ENST00000575331.1	TSL:1	n.4893A>G		non_coding_transcript_exon	Exon 3 of 3
CHRNB1	ENST00000572857.5	TSL:4	c.95A>G	p.Glu32Gly	missense	Exon 2 of 6	ENSP00000461402.1

Frequencies

GnomAD3 genomes

AF:

0.242

AC:

36844

AN:

151998

Hom.:

6033

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0631

Gnomad AMI

AF:

0.396

Gnomad AMR

AF:

0.233

Gnomad ASJ

AF:

0.355

Gnomad EAS

AF:

0.00251

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.275

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.367

Gnomad OTH

AF:

0.282

GnomAD2 exomes

AF:

0.248

AC:

60334

AN:

243398

AF XY:

0.254

show subpopulations

Gnomad AFR exome

AF:

0.0517

Gnomad AMR exome

AF:

0.164

Gnomad ASJ exome

AF:

0.350

Gnomad EAS exome

AF:

0.000658

Gnomad FIN exome

AF:

0.272

Gnomad NFE exome

AF:

0.364

Gnomad OTH exome

AF:

0.291

GnomAD4 exome

AF:

0.327

AC:

478142

AN:

1460072

Hom.:

85718

Cov.:

AF XY:

0.323

AC XY:

234714

AN XY:

726302

show subpopulations

African (AFR)

AF:

0.0523

AC:

1749

AN:

33464

American (AMR)

AF:

0.171

AC:

7638

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.357

AC:

9318

AN:

26110

East Asian (EAS)

AF:

0.000655

AC:

AN:

39678

South Asian (SAS)

AF:

0.121

AC:

10433

AN:

86198

European-Finnish (FIN)

AF:

0.278

AC:

14608

AN:

52548

Middle Eastern (MID)

AF:

0.321

AC:

1853

AN:

5768

European-Non Finnish (NFE)

AF:

0.373

AC:

414317

AN:

1111426

Other (OTH)

AF:

0.302

AC:

18200

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

20258

40516

60774

81032

101290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12572

25144

37716

50288

62860

<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:

0.242

AC:

36826

AN:

152116

Hom.:

6030

Cov.:

AF XY:

0.234

AC XY:

17413

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0630

AC:

2613

AN:

41506

American (AMR)

AF:

0.233

AC:

3561

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.355

AC:

1232

AN:

3472

East Asian (EAS)

AF:

0.00252

AC:

AN:

5162

South Asian (SAS)

AF:

0.112

AC:

539

AN:

4824

European-Finnish (FIN)

AF:

0.275

AC:

2911

AN:

10590

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.367

AC:

24907

AN:

67956

Other (OTH)

AF:

0.279

AC:

588

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1336

2673

4009

5346

6682

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

358

716

1074

1432

1790

<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:

0.332

Hom.:

14866

Bravo

AF:

0.231

TwinsUK

AF:

0.379

AC:

1404

ALSPAC

AF:

0.369

AC:

1422

ESP6500AA

AF:

0.0641

AC:

282

ESP6500EA

AF:

0.354

AC:

3042

ExAC

AF:

0.244

AC:

29534

Asia WGS

AF:

0.0540

AC:

186

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 07, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Feb 14, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Congenital myasthenic syndrome 2A

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Congenital myasthenic syndrome 4C

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.95

MetaRNN

Benign

0.0032

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

6.1

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.32

Sift

Benign

0.26

Sift4G

Benign

0.18

Polyphen

0.77

Vest4

0.11

MPC

0.70

ClinPred

0.037

GERP RS

5.4

PromoterAI

0.037

Neutral

(source)

Varity_R

0.24

gMVP

0.53

Mutation Taster

=88/12

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over