1-154568048-G-T

Variant names:

• chr1-154568048-G-T
• NM_000748.3:c.4G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000748.3(CHRNB2):​c.4G>T​(p.Ala2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CHRNB2 NM_000748.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.770
• 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

ENSG00000286391 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18175316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB2	NM_000748.3	c.4G>T	p.Ala2Ser	missense_variant	Exon 1 of 6	ENST00000368476.4	NP_000739.1
CHRNB2	XR_001736952.3	n.271G>T		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB2	ENST00000368476.4	c.4G>T	p.Ala2Ser	missense_variant	Exon 1 of 6	1	NM_000748.3	ENSP00000357461.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442922 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 716584

African (AFR) AF: 0.00 AC: 0 AN: 33148

American (AMR) AF: 0.00 AC: 0 AN: 42916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25706

East Asian (EAS) AF: 0.00 AC: 0 AN: 38804

South Asian (SAS) AF: 0.00 AC: 0 AN: 83458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105112

Other (OTH) AF: 0.00 AC: 0 AN: 59590

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

Apr 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with CHRNB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1439535). 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. 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2 of the CHRNB2 protein (p.Ala2Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.35	N;.
PhyloP100		0.77
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.26	N;.
REVEL	Benign	0.24
Sift	Benign	0.13	T;.
Sift4G	Benign	0.16	T;.
Polyphen		0.0	B;.
Vest4		0.18
MutPred		0.19		Gain of phosphorylation at A2 (P = 0.0429);Gain of phosphorylation at A2 (P = 0.0429);
MVP		0.78
MPC		1.0
ClinPred		0.15	T
GERP RS		2.3
PromoterAI		-0.051	Neutral
Varity_R		0.044
gMVP		0.48
Mutation Taster		=92/8	polymorphism

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

hg19: chr1-154540524; COSMIC: COSV63809175; COSMIC: COSV63809175;