rs916448473

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_000748.3(CHRNB2):c.1312A>G(p.Met438Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000052 in 1,537,908 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. M438I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000051 ( 0 hom. )

Consequence

CHRNB2
NM_000748.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.63

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30169713).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB2	NM_000748.3 link	c.1312A>G	p.Met438Val	missense_variant	Exon 5 of 6	ENST00000368476.4	NP_000739.1	P17787Q5SXY3
CHRNB2	XM_017000180.3 link	c.802A>G	p.Met268Val	missense_variant	Exon 2 of 3		XP_016855669.1
CHRNB2	XR_001736952.3 link	n.1579A>G		non_coding_transcript_exon_variant	Exon 5 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHRNB2	ENST00000368476.4 link	c.1312A>G	p.Met438Val	missense_variant	Exon 5 of 6	1	NM_000748.3	ENSP00000357461.3	P17787
CHRNB2	ENST00000637900.1 link	c.1318A>G	p.Met440Val	missense_variant	Exon 5 of 6	5		ENSP00000490474.1	A0A1B0GVD7
CHRNB2	ENST00000636034.1 link	n.1312A>G		non_coding_transcript_exon_variant	Exon 5 of 9	5		ENSP00000489703.1	A0A1B0GTH5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000505

AC:

AN:

1385696

Hom.:

Cov.:

AF XY:

0.00000731

AC XY:

AN XY:

683934

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31546

American (AMR)

AF:

0.00

AC:

AN:

35686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25164

East Asian (EAS)

AF:

0.00

AC:

AN:

35720

South Asian (SAS)

AF:

0.00

AC:

AN:

79190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4964

European-Non Finnish (NFE)

AF:

0.00000649

AC:

AN:

1078660

Other (OTH)

AF:

0.00

AC:

AN:

57808

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

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

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 07, 2016

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant nocturnal frontal lobe epilepsy

Uncertain:1

Oct 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals affected with CHRNB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 438 of the CHRNB2 protein (p.Met438Val). ClinVar contains an entry for this variant (Variation ID: 447038). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CHRNB2 protein function. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

0.0068

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.73

D;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.5

L;.

PhyloP100

3.6

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.6

D;.

REVEL

Uncertain

0.30

Sift

Benign

0.17

T;.

Sift4G

Benign

0.24

T;.

Polyphen

0.0

B;.

Vest4

0.29

MutPred

0.66

Loss of helix (P = 0.1299);.;

MVP

0.74

MPC

1.1

ClinPred

0.60

GERP RS

1.5

Varity_R

0.43

gMVP

0.84

Mutation Taster

=83/17

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over