rs55857552

chr1-154572056-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -5.66

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High AC in GnomAd at 480 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 480 AN: 152214 Hom.: 2 Cov.: 32

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.: 0 AF XY: 0.00287 AC XY: 201 AN XY: 70102

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.: 19 Cov.: 33 AF XY: 0.00537 AC XY: 3659 AN XY: 681908

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.: 2 Cov.: 32 AF XY: 0.00277 AC XY: 206 AN XY: 74480

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.: 0

Bravo AF: 0.00328

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 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	- -

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

Invitae

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, criteria provided, single submitter

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

Other links and lift over

dbSNP: rs55857552; hg19: chr1-154544532;