rs202079239

chr1-154575801-C-Gchr1-154575801-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000748.3(CHRNB2):c.1378C>G(p.Arg460Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000455 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R460C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: CHRNB2 NM_000748.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 2.12

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 -16 ACMG points.

• BP6: Variant 1-154575801-C-G is Benign according to our data. Variant chr1-154575801-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 191352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154575801-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000335 (51/152228) while in subpopulation NFE AF= 0.000382 (26/68014). AF 95% confidence interval is 0.000267. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB2	NM_000748.3	c.1378C>G	p.Arg460Gly	missense_variant	6/6	ENST00000368476.4
CHRNB2	XM_017000180.3	c.868C>G	p.Arg290Gly	missense_variant	3/3
CHRNB2	XR_001736952.3	n.1645C>G		non_coding_transcript_exon_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB2	ENST00000368476.4	c.1378C>G	p.Arg460Gly	missense_variant	6/6	1	NM_000748.3	P4
CHRNB2	ENST00000637900.1	c.1384C>G	p.Arg462Gly	missense_variant	6/6	5		A1
CHRNB2	ENST00000636034.1	c.1378C>G	p.Arg460Gly	missense_variant, NMD_transcript_variant	6/9	5

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000342 AC: 86 AN: 251478 Hom.: 0 AF XY: 0.000272 AC XY: 37 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00236

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000468 AC: 684 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.000450 AC XY: 327 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00228

Gnomad4 NFE exome AF: 0.000483

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74434

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000384 Hom.: 0

Bravo AF: 0.000170

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2019	This variant is associated with the following publications: (PMID: 26475232) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -

Generalized-onset seizure Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Medical Genetics, Oslo University Hospital

Dec 22, 2014

- -

Autosomal dominant nocturnal frontal lobe epilepsy 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 20, 2021

- -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.5	D;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.89
MVP		0.98
MPC		0.73
ClinPred		0.40	T
GERP RS		5.2
Varity_R		0.98
gMVP		0.96

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: rs202079239; hg19: chr1-154548277;