1-154572014-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000748.3(CHRNB2):c.1191G>C(p.Gln397His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,533,948 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. Q397P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0067 ( 7 hom., cov: 32)

Exomes 𝑓: 0.012 ( 114 hom. )

Consequence

CHRNB2
NM_000748.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 0.149

Publications

7 publications found

Variant links:

Genes affected

CHRNB2 (HGNC:1962): (cholinergic receptor nicotinic beta 2 subunit) Neuronal acetylcholine receptors are homo- or heteropentameric complexes composed of homologous alpha and beta subunits. They belong to a superfamily of ligand-gated ion channels which allow the flow of sodium and potassium across the plasma membrane in response to ligands such as acetylcholine and nicotine. This gene encodes one of several beta subunits. Mutations in this gene are associated with autosomal dominant nocturnal frontal lobe epilepsy. [provided by RefSeq, Jul 2008]

CHRNB2 Gene-Disease associations (from GenCC):

familial sleep-related hypermotor epilepsy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal dominant nocturnal frontal lobe epilepsy 3
Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
autosomal dominant nocturnal frontal lobe epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CHRNB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069208145).

BP6

Variant 1-154572014-G-C is Benign according to our data. Variant chr1-154572014-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158330.

BS2

High AC in GnomAd4 at 1014 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000748.3. 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
	CHRNB2	NM_000748.3	MANE Select	c.1191G>C	p.Gln397His	missense	Exon 5 of 6	NP_000739.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHRNB2	ENST00000368476.4	TSL:1 MANE Select	c.1191G>C	p.Gln397His	missense	Exon 5 of 6	ENSP00000357461.3
CHRNB2	ENST00000637900.1	TSL:5	c.1197G>C	p.Gln399His	missense	Exon 5 of 6	ENSP00000490474.1
CHRNB2	ENST00000636034.1	TSL:5	n.1191G>C		non_coding_transcript_exon	Exon 5 of 9	ENSP00000489703.1

Frequencies

GnomAD3 genomes

AF:

0.00666

AC:

1014

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00517

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00227

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0114

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00583

AC:

757

AN:

129764

AF XY:

0.00556

show subpopulations

Gnomad AFR exome

AF:

0.00194

Gnomad AMR exome

AF:

0.00374

Gnomad ASJ exome

AF:

0.000623

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00162

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.00673

GnomAD4 exome

AF:

0.0120

AC:

16598

AN:

1381564

Hom.:

114

Cov.:

AF XY:

0.0117

AC XY:

7948

AN XY:

681480

show subpopulations

African (AFR)

AF:

0.00213

AC:

AN:

31460

American (AMR)

AF:

0.00377

AC:

134

AN:

35532

Ashkenazi Jewish (ASJ)

AF:

0.000519

AC:

AN:

25046

East Asian (EAS)

AF:

0.00

AC:

AN:

35644

South Asian (SAS)

AF:

0.00262

AC:

207

AN:

79072

European-Finnish (FIN)

AF:

0.00252

AC:

AN:

34878

Middle Eastern (MID)

AF:

0.000561

AC:

AN:

5350

European-Non Finnish (NFE)

AF:

0.0144

AC:

15498

AN:

1076920

Other (OTH)

AF:

0.0102

AC:

588

AN:

57662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1101

2202

3302

4403

5504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

602

1204

1806

2408

3010

<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:

0.00665

AC:

1014

AN:

152384

Hom.:

Cov.:

AF XY:

0.00617

AC XY:

460

AN XY:

74524

show subpopulations

African (AFR)

AF:

0.00274

AC:

114

AN:

41594

American (AMR)

AF:

0.00516

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00228

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0114

AC:

774

AN:

68034

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

118

177

236

295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00703

Hom.:

Bravo

AF:

0.00711

ESP6500AA

AF:

0.000644

AC:

ESP6500EA

AF:

0.00544

AC:

ExAC

AF:

0.00223

AC:

180

Asia WGS

AF:

0.00173

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Jul 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.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 14, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:3

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CHRNB2: BS1, BS2

Dec 01, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 09, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal dominant nocturnal frontal lobe epilepsy 3

Uncertain:1

Jan 15, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

May 28, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.27

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.54

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.0069

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.36

PhyloP100

0.15

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.37

REVEL

Benign

0.25

Sift

Benign

0.24

Sift4G

Benign

0.28

Polyphen

0.0

Vest4

0.31

MutPred

0.13

Gain of catalytic residue at L399 (P = 0.0997)

MVP

0.66

MPC

1.0

ClinPred

0.0037

GERP RS

2.8

Varity_R

0.11

gMVP

0.69

Mutation Taster

=95/5

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over