rs74315291

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-154571682-G-A
• chr1-154571682-G-C
• chr1-154571682-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000748.3(CHRNB2):​c.859G>A​(p.Val287Met) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V287L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRNB2 NM_000748.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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 14 ACMG points.

• 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-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1707538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant 1-154571682-G-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB2	NM_000748.3	c.859G>A	p.Val287Met	missense_variant	Exon 5 of 6	ENST00000368476.4	NP_000739.1
CHRNB2	XM_017000180.3	c.349G>A	p.Val117Met	missense_variant	Exon 2 of 3		XP_016855669.1
CHRNB2	XR_001736952.3	n.1126G>A		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.859G>A	p.Val287Met	missense_variant	Exon 5 of 6	1	NM_000748.3	ENSP00000357461.3
CHRNB2	ENST00000637900.1	c.865G>A	p.Val289Met	missense_variant	Exon 5 of 6	5		ENSP00000490474.1
CHRNB2	ENST00000636034.1	n.859G>A		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: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy 3 Pathogenic:2

Mar 30, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PS1, PM5_STR, PS3_MOD, PS4_MOD, PP1_MOD, PM2_SUP, PP3 -

Jan 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Autosomal dominant nocturnal frontal lobe epilepsy 1 Pathogenic:1

Jan 30, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4,PM5_STR,PS3_MOD,PP1_MOD,PM2_SUP,PP3 -

Autosomal dominant nocturnal frontal lobe epilepsy Pathogenic:1

Jun 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individuals with autosomal dominant nocturnal frontal lobe epilepsy (PMID: 11104662, 17900292). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17496). 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. Experimental studies have shown that this missense change affects CHRNB2 function (PMID: 11104662, 18456869, 22036597). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 287 of the CHRNB2 protein (p.Val287Met). -

Inborn genetic diseases Pathogenic:1

Feb 16, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.859G>A (p.V287M) alteration is located in exon 5 (coding exon 5) of the CHRNB2 gene. This alteration results from a G to A substitution at nucleotide position 859, causing the valine (V) at amino acid position 287 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported to segregate in two large families with varying severities of sleep-related hypermotor epilepsy and showed incomplete penetrance (Phillips, 2001; Díaz-Otero, 2008). Another alteration at the same codon, c.859G>C (p.V287L), has been described in a large family with nocturnal frontal lobe epilepsy (De Fusco, 2000). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). In two assays testing desensitization properties, this variant showed functionally altered results (Phillips, 2001; Hoda, 2008). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Oct 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.5	L;.
PhyloP100		6.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.4	N;.
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.91		Loss of catalytic residue at V287 (P = 0.0319);.;
MVP		0.95
MPC		2.3
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.92
gMVP		0.88
Mutation Taster		=38/62	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; COSMIC: COSV105924407; COSMIC: COSV105924407;