chr1-154572058-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000748.3(CHRNB2):c.1235G>A(p.Gly412Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,534,646 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. G412S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 4 hom. )

Consequence

CHRNB2
NM_000748.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.65

Publications

1 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019599497).

BP6

Variant 1-154572058-G-A is Benign according to our data. Variant chr1-154572058-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 205060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 188 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CHRNB2	NM_000748.3 link	c.1235G>A	p.Gly412Asp	missense_variant	Exon 5 of 6	ENST00000368476.4	NP_000739.1
CHRNB2	XM_017000180.3 link	c.725G>A	p.Gly242Asp	missense_variant	Exon 2 of 3		XP_016855669.1
CHRNB2	XR_001736952.3 link	n.1502G>A		non_coding_transcript_exon_variant	Exon 5 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CHRNB2	ENST00000368476.4 link	c.1235G>A	p.Gly412Asp	missense_variant	Exon 5 of 6	1	NM_000748.3	ENSP00000357461.3
CHRNB2	ENST00000637900.1 link	c.1241G>A	p.Gly414Asp	missense_variant	Exon 5 of 6	5		ENSP00000490474.1
CHRNB2	ENST00000636034.1 link	n.1235G>A		non_coding_transcript_exon_variant	Exon 5 of 9	5		ENSP00000489703.1

Frequencies

GnomAD3 genomes

AF:

0.00124

AC:

188

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00207

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00125

AC:

161

AN:

128840

AF XY:

0.00105

show subpopulations

Gnomad AFR exome

AF:

0.000163

Gnomad AMR exome

AF:

0.00234

Gnomad ASJ exome

AF:

0.000498

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000339

Gnomad NFE exome

AF:

0.00189

Gnomad OTH exome

AF:

0.00175

GnomAD4 exome

AF:

0.00207

AC:

2858

AN:

1382320

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

1332

AN XY:

682068

show subpopulations

African (AFR)

AF:

0.000317

AC:

AN:

31524

American (AMR)

AF:

0.00211

AC:

AN:

35592

Ashkenazi Jewish (ASJ)

AF:

0.000239

AC:

AN:

25076

East Asian (EAS)

AF:

0.00

AC:

AN:

35686

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79098

European-Finnish (FIN)

AF:

0.000953

AC:

AN:

34628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5244

European-Non Finnish (NFE)

AF:

0.00244

AC:

2635

AN:

1077728

Other (OTH)

AF:

0.00170

AC:

AN:

57744

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

198

396

593

791

989

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

294

392

490

<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:

0.00123

AC:

188

AN:

152326

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000601

AC:

AN:

41586

American (AMR)

AF:

0.00105

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00207

AC:

141

AN:

68022

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00169

Hom.:

Bravo

AF:

0.00153

ESP6500AA

AF:

0.000374

AC:

ESP6500EA

AF:

0.000532

AC:

ExAC

AF:

0.000278

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Aug 14, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 19, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4, BP6; This alteration is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory).

not provided

Benign:2

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CHRNB2: BS1

Apr 23, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal dominant nocturnal frontal lobe epilepsy 3

Benign:1

Sep 28, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.2% (141/68030) (https://gnomad.broadinstitute.org/variant/1-154572058-G-A?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:205060). Evolutionary conservation for this variant is limited or unavailable; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign.

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Nov 16, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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.

CHRNB2-related disorder

Benign:1

Sep 17, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.28

T;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.89

LIST_S2

Benign

0.16

T;T

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.46

N;.

PhyloP100

2.6

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.64

N;.

Sift

Benign

0.21

T;.

Sift4G

Benign

0.48

T;.

Vest4

0.41

ClinPred

0.0071

GERP RS

2.9

Varity_R

0.049

gMVP

0.65

Mutation Taster

=90/10

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over