rs752986234

chr1-154571514-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_000748.3(CHRNB2):c.691C>T(p.Arg231Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R231R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CHRNB2 NM_000748.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.37

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 Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864
• BS2: High AC in GnomAdExome at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB2	NM_000748.3	c.691C>T	p.Arg231Cys	missense_variant	5/6	ENST00000368476.4
CHRNB2	XM_017000180.3	c.181C>T	p.Arg61Cys	missense_variant	2/3
CHRNB2	XR_001736952.3	n.958C>T		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB2	ENST00000368476.4	c.691C>T	p.Arg231Cys	missense_variant	5/6	1	NM_000748.3	P4
CHRNB2	ENST00000637900.1	c.697C>T	p.Arg233Cys	missense_variant	5/6	5		A1
CHRNB2	ENST00000636034.1	c.691C>T	p.Arg231Cys	missense_variant, NMD_transcript_variant	5/9	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 251136 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461680 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74308

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 27, 2020

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The frequency data for this variant (rs752986234) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a CHRNB2-related disease. This sequence change replaces arginine with cysteine at codon 231 of the CHRNB2 protein (p.Arg231Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.4	D;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.62
MutPred		0.74		Gain of ubiquitination at K233 (P = 0.0726);.;
MVP		0.89
MPC		2.6
ClinPred		0.98	D
GERP RS		3.2
Varity_R		0.82
gMVP		0.93

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: rs752986234; hg19: chr1-154543990;