1-154571682-G-C

Position:

• chr1-154571682-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_Very_Strong PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000748.3(CHRNB2):​c.859G>C​(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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely 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 criteria provided, single submitter P:2
• 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]

CHRNB2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PS1: Transcript NM_000748.3 (CHRNB2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1707538
• 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, 0.867
• PP5: Variant 1-154571682-G-C is Pathogenic according to our data. Variant chr1-154571682-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 17495.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNB2	NM_000748.3	c.859G>C	p.Val287Leu	missense_variant	5/6	ENST00000368476.4	NP_000739.1
CHRNB2	XM_017000180.3	c.349G>C	p.Val117Leu	missense_variant	2/3		XP_016855669.1
CHRNB2	XR_001736952.3	n.1126G>C		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNB2	ENST00000368476.4	c.859G>C	p.Val287Leu	missense_variant	5/6	1	NM_000748.3	ENSP00000357461.3
CHRNB2	ENST00000637900.1	c.865G>C	p.Val289Leu	missense_variant	5/6	5		ENSP00000490474.1
CHRNB2	ENST00000636034.1	n.859G>C		non_coding_transcript_exon_variant	5/9	5		ENSP00000489703.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2000

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 2023

Published transgenic mouse and rat models harboring this variant demonstrate spontaneous seizures during periods of increased EEG delta wave activity which would correlate with slow-wave sleep in humans (Manfredi et al., 2009; Shiba et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19237585, 20603624, 11062464, 27336596, 25565544, 28717674, 11512019, 15245761, 23934645, 18342259, 33924731, 15843070, 17662253, 12015163, 22897520, 21704022, 36835631, 17900292, 26072248, 21091316, 12681012, 12773798, 11952766, 15130686, 33689168, 23123803, 26309560, 33284031, 28761347, 33255633, 26561946, 35513164, 11893908, 16815873, 36796465, 12887446, 12782965, 12823585, 25104926, 11579434, 26091610, 11904236, 19153075) -

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	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.7	L;.
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;