chr1-154572056-G-A

Position:

chr1-154572056-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000748.3(CHRNB2):c.1233G>A(p.Ala411=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00526 in 1,534,416 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0055 ( 19 hom. )

Consequence

CHRNB2
NM_000748.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -5.66

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 1-154572056-G-A is Benign according to our data. Variant chr1-154572056-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154572056-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-5.66 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00316 (481/152326) while in subpopulation NFE AF= 0.0055 (374/68006). AF 95% confidence interval is 0.00504. There are 2 homozygotes in gnomad4. There are 206 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 481 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CHRNB2	NM_000748.3 linkuse as main transcript	c.1233G>A	p.Ala411=	synonymous_variant	5/6	ENST00000368476.4	NP_000739.1
CHRNB2	XM_017000180.3 linkuse as main transcript	c.723G>A	p.Ala241=	synonymous_variant	2/3		XP_016855669.1
CHRNB2	XR_001736952.3 linkuse as main transcript	n.1500G>A		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CHRNB2	ENST00000368476.4 linkuse as main transcript	c.1233G>A	p.Ala411=	synonymous_variant	5/6	1	NM_000748.3	ENSP00000357461	P4
CHRNB2	ENST00000637900.1 linkuse as main transcript	c.1239G>A	p.Ala413=	synonymous_variant	5/6	5		ENSP00000490474	A1
CHRNB2	ENST00000636034.1 linkuse as main transcript	c.1233G>A	p.Ala411=	synonymous_variant, NMD_transcript_variant	5/9	5		ENSP00000489703

Frequencies

GnomAD3 genomes

AF:

0.00315

AC:

480

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00550

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00295

AC:

378

AN:

128088

Hom.:

AF XY:

0.00287

AC XY:

201

AN XY:

70102

show subpopulations

Gnomad AFR exome

AF:

0.000654

Gnomad AMR exome

AF:

0.00272

Gnomad ASJ exome

AF:

0.00164

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00122

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.00517

Gnomad OTH exome

AF:

0.00427

GnomAD4 exome

AF:

0.00549

AC:

7593

AN:

1382090

Hom.:

Cov.:

AF XY:

0.00537

AC XY:

3659

AN XY:

681908

show subpopulations

Gnomad4 AFR exome

AF:

0.000857

Gnomad4 AMR exome

AF:

0.00292

Gnomad4 ASJ exome

AF:

0.00128

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00126

Gnomad4 FIN exome

AF:

0.00121

Gnomad4 NFE exome

AF:

0.00650

Gnomad4 OTH exome

AF:

0.00480

GnomAD4 genome

AF:

0.00316

AC:

481

AN:

152326

Hom.:

Cov.:

AF XY:

0.00277

AC XY:

206

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00550

Gnomad4 OTH

AF:

0.00614

Alfa

AF:

0.00294

Hom.:

Bravo

AF:

0.00328

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CHRNB2: BP4, BP7, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 01, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 18, 2017	- -

Autosomal dominant nocturnal frontal lobe epilepsy 3

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 21, 2021	- -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2022

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. -

CHRNB2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2019

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

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.16

DANN

Benign

0.69

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