1-154571682-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000748.3(CHRNB2):c.859G>T(p.Val287Leu) variant causes a missense change. 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V287M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRNB2 NM_000748.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.85

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 Pathogenic. Variant got 18 ACMG points.

• PS1: Transcript NM_000748.3 (CHRNB2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 17495
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-154571682-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866
• PP5: Variant 1-154571682-G-T is Pathogenic according to our data. Variant chr1-154571682-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1707538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB2	NM_000748.3	c.859G>T	p.Val287Leu	missense_variant	5/6	ENST00000368476.4
CHRNB2	XM_017000180.3	c.349G>T	p.Val117Leu	missense_variant	2/3
CHRNB2	XR_001736952.3	n.1126G>T		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB2	ENST00000368476.4	c.859G>T	p.Val287Leu	missense_variant	5/6	1	NM_000748.3	P4
CHRNB2	ENST00000637900.1	c.865G>T	p.Val289Leu	missense_variant	5/6	5		A1
CHRNB2	ENST00000636034.1	c.859G>T	p.Val287Leu	missense_variant, NMD_transcript_variant	5/9	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy 3 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 10, 2023	Variant summary: CHRNB2 c.859G>T (p.Val287Leu) results in a conservative amino acid change located in the Neurotransmitter-gated ion-channel transmembrane domain (IPR006029) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251228 control chromosomes (gnomAD). c.859G>T has been reported in the literature in multiple individuals affected with autosomal dominant nocturnal frontal lobe epilepsy (DeFusco_2000, Picard_2008, Labate_2012) and this variant co-segregated with disease (DeFusco_2000, Labate_2012). These data indicate that the variant is very likely to be associated with disease. At least two publication report this variant alters the subunit composition and sensitivity of 42 nAChRs, and increases 542 surface expression (DeFusco_2000, Nichols_2016). The following publications have been ascertained in the context of this evaluation (PMID: 22897520, 19059498, 19237585, 22036597, 27336596). Two ClinVar submitters (evaluation after 2014) cite this variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 16, 2022	_x000D_ Criteria applied: PS1, PM1, PM5, PM2_SUP -

Autosomal dominant nocturnal frontal lobe epilepsy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 25, 2022

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 287 of the CHRNB2 protein (p.Val287Leu). 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val287 amino acid residue in CHRNB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11104662, 17900292). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 41033). This missense change has been observed in individual(s) with autosomal dominant nocturnal frontal lobe epilepsy (PMID: 11062464). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.9	N;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;.
Sift4G	Benign	0.074	T;.
Polyphen		0.94	P;.
Vest4		0.87
MutPred		0.88		Loss of methylation at K285 (P = 0.0831);.;
MVP		0.96
MPC		2.2
ClinPred		0.96	D
GERP RS		4.0
Varity_R		0.94
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: rs74315291; hg19: chr1-154544158;