chr1-154572058-G-A

Position:

chr1-154572058-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 13/21 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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 [Likely_benign]. Clinvar id is 205060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154572058-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00123 (188/152326) while in subpopulation NFE AF= 0.00207 (141/68022). AF 95% confidence interval is 0.00179. There are 0 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 188 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CHRNB2	NM_000748.3 linkuse as main transcript	c.1235G>A	p.Gly412Asp	missense_variant	5/6	ENST00000368476.4
CHRNB2	XM_017000180.3 linkuse as main transcript	c.725G>A	p.Gly242Asp	missense_variant	2/3
CHRNB2	XR_001736952.3 linkuse as main transcript	n.1502G>A		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CHRNB2	ENST00000368476.4 linkuse as main transcript	c.1235G>A	p.Gly412Asp	missense_variant	5/6	1	NM_000748.3	P4
CHRNB2	ENST00000637900.1 linkuse as main transcript	c.1241G>A	p.Gly414Asp	missense_variant	5/6	5		A1
CHRNB2	ENST00000636034.1 linkuse as main transcript	c.1235G>A	p.Gly412Asp	missense_variant, NMD_transcript_variant	5/9	5

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

GnomAD3 exomes

AF:

0.00125

AC:

161

AN:

128840

Hom.:

AF XY:

0.00105

AC XY:

AN XY:

70570

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 SAS 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

Gnomad4 AFR exome

AF:

0.000317

Gnomad4 AMR exome

AF:

0.00211

Gnomad4 ASJ exome

AF:

0.000239

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.000953

Gnomad4 NFE exome

AF:

0.00244

Gnomad4 OTH exome

AF:

0.00170

GnomAD4 genome

AF:

0.00123

AC:

188

AN:

152326

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000601

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00207

Gnomad4 OTH

AF:

0.000945

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

Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Oct 19, 2017	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). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 16, 2017	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	CHRNB2: PP2, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2019	- -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Autosomal dominant nocturnal frontal lobe epilepsy 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Sep 28, 2022

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. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2020

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

DANN

Benign

0.54

DEOGEN2

Benign

0.28

T;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.089

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;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.64

N;.

REVEL

Uncertain

0.35

Sift

Benign

0.21

T;.

Sift4G

Benign

0.48

T;.

Polyphen

0.021

B;.

Vest4

0.41

MVP

0.79

MPC

1.5

ClinPred

0.0071

GERP RS

2.9

Varity_R

0.049

gMVP

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over