Genetic Variant CHRNB2:p.Gly412Arg (chr1-154572057-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000748.3(CHRNB2):c.1234G>C(p.Gly412Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,382,224 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G412D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

CHRNB2
NM_000748.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.94

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19661853).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB2	NM_000748.3	MANE Select	c.1234G>C	p.Gly412Arg	missense	Exon 5 of 6	NP_000739.1	P17787

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRNB2	ENST00000368476.4	TSL:1 MANE Select	c.1234G>C	p.Gly412Arg	missense	Exon 5 of 6	ENSP00000357461.3	P17787
CHRNB2	ENST00000637900.1	TSL:5	c.1240G>C	p.Gly414Arg	missense	Exon 5 of 6	ENSP00000490474.1	A0A1B0GVD7
CHRNB2	ENST00000636034.1	TSL:5	n.1234G>C		non_coding_transcript_exon	Exon 5 of 9	ENSP00000489703.1	A0A1B0GTH5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.23e-7

AC:

AN:

1382224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

682004

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31518

American (AMR)

AF:

0.00

AC:

AN:

35584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25074

East Asian (EAS)

AF:

0.00

AC:

AN:

35680

South Asian (SAS)

AF:

0.00

AC:

AN:

79090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34640

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5250

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1077650

Other (OTH)

AF:

0.00

AC:

AN:

57738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.31

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.22

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.77

PhyloP100

1.9

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.46

REVEL

Uncertain

0.32

Sift

Benign

0.26

Sift4G

Benign

0.41

Polyphen

0.0

Vest4

0.40

MutPred

0.48

Loss of catalytic residue at A411 (P = 0.0487)

MVP

0.76

MPC

1.3

ClinPred

0.11

GERP RS

3.9

Varity_R

0.085

gMVP

0.59

Mutation Taster

=84/16

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over