NM_000748.3:c.539G>C

Variant names:

• chr1-154571362-G-C
• rs768297928
• NM_000748.3:c.539G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000748.3(CHRNB2):​c.539G>C​(p.Arg180Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R180L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRNB2 NM_000748.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• familial sleep-related hypermotor epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nocturnal frontal lobe epilepsy 3

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB2	NM_000748.3	c.539G>C	p.Arg180Pro	missense_variant	Exon 5 of 6	ENST00000368476.4	NP_000739.1
CHRNB2	XM_017000180.3	c.29G>C	p.Arg10Pro	missense_variant	Exon 2 of 3		XP_016855669.1
CHRNB2	XR_001736952.3	n.806G>C		non_coding_transcript_exon_variant	Exon 5 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB2	ENST00000368476.4	c.539G>C	p.Arg180Pro	missense_variant	Exon 5 of 6	1	NM_000748.3	ENSP00000357461.3
CHRNB2	ENST00000637900.1	c.545G>C	p.Arg182Pro	missense_variant	Exon 5 of 6	5		ENSP00000490474.1
CHRNB2	ENST00000636034.1	n.539G>C		non_coding_transcript_exon_variant	Exon 5 of 9	5		ENSP00000489703.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Uncertain:1

Jul 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CHRNB2 protein function. ClinVar contains an entry for this variant (Variation ID: 1522372). This variant has not been reported in the literature in individuals affected with CHRNB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 180 of the CHRNB2 protein (p.Arg180Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.065	T
MutationAssessor	Benign	1.6	L;.
PhyloP100		3.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.013	D;.
Sift4G	Uncertain	0.044	D;.
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.69		Loss of sheet (P = 0.0817);.;
MVP		0.86
MPC		2.6
ClinPred		0.97	D
GERP RS		3.5
Varity_R		0.79
gMVP		0.96
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs768297928; hg19: chr1-154543838; COSMIC: COSV100872666; COSMIC: COSV100872666;