rs112585933

Positions:

• chr1-154572058-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.65

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 -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	UniProt
CHRNB2	NM_000748.3	c.1235G>A	p.Gly412Asp	missense_variant	5/6	ENST00000368476.4
CHRNB2	XM_017000180.3	c.725G>A	p.Gly242Asp	missense_variant	2/3
CHRNB2	XR_001736952.3	n.1502G>A		non_coding_transcript_exon_variant	5/7

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 188 AN: 152214 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00105 AC XY: 74 AN XY: 70570

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.: 4 Cov.: 33 AF XY: 0.00195 AC XY: 1332 AN XY: 682068

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.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74478

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.: 0

Bravo AF: 0.00153

ESP6500AA AF: 0.000374 AC: 1

ESP6500EA AF: 0.000532 AC: 3

ExAC AF: 0.000278 AC: 16

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

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	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	14
DANN	Benign	0.54
DEOGEN2	Benign	0.28	T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.16	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.020	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.46	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.77	T
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	T
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

Other links and lift over

dbSNP: rs112585933; hg19: chr1-154544534;