NM_000748.3:c.859G>C

Variant names:

• chr1-154571682-G-C
• rs74315291
• NM_000748.3:c.859G>C

Variant summary

Our verdict is Pathogenic. The variant received 26 ACMG points: 26P and 0B. PS1_Very_Strong PS3 PM2 PM5 PP3_Moderate PP5_Very_Strong

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 (★★). ClinVar reports functional evidence for this variant: "SCV005201743: 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" and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in 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, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.85
• Publications: 21 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: Pathogenic. The variant received 26 ACMG points.

• PS1: Transcript NM_000748.3 (CHRNB2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005201743: 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)
• 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 VariationId 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 VariationId is 17495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000748.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB2	NM_000748.3	MANE Select	c.859G>C	p.Val287Leu	missense	Exon 5 of 6	NP_000739.1	P17787

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB2	ENST00000368476.4	TSL:1 MANE Select	c.859G>C	p.Val287Leu	missense	Exon 5 of 6	ENSP00000357461.3	P17787
	CHRNB2	ENST00000637900.1	TSL:5	c.865G>C	p.Val289Leu	missense	Exon 5 of 6	ENSP00000490474.1	A0A1B0GVD7
	CHRNB2	ENST00000636034.1	TSL:5	n.859G>C		non_coding_transcript_exon	Exon 5 of 9	ENSP00000489703.1	A0A1B0GTH5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Autosomal dominant nocturnal frontal lobe epilepsy 3 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.8
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
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs74315291; hg19: chr1-154544158;