NM_000748.3:c.1233G>A

Variant names:

• chr1-154572056-G-A
• rs55857552
• NM_000748.3:c.1233G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000748.3(CHRNB2):​c.1233G>A​(p.Ala411Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00526 in 1,534,416 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (19 hom.)
• Consequence: CHRNB2 NM_000748.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -5.66
• Publications: 6 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 1-154572056-G-A is Benign according to our data. Variant chr1-154572056-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.66 with no splicing effect.
• BS2: High AC in GnomAd4 at 481 AD gene.

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.1233G>A	p.Ala411Ala	synonymous	Exon 5 of 6	NP_000739.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB2	ENST00000368476.4	TSL:1 MANE Select	c.1233G>A	p.Ala411Ala	synonymous	Exon 5 of 6	ENSP00000357461.3
	CHRNB2	ENST00000637900.1	TSL:5	c.1239G>A	p.Ala413Ala	synonymous	Exon 5 of 6	ENSP00000490474.1
	CHRNB2	ENST00000636034.1	TSL:5	n.1233G>A		non_coding_transcript_exon	Exon 5 of 9	ENSP00000489703.1

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 480 AN: 152214 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00295 AC: 378 AN: 128088 AF XY: 0.00287

Gnomad AFR exome AF: 0.000654

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00164

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00517

Gnomad OTH exome AF: 0.00427

GnomAD4 exome AF: 0.00549 AC: 7593 AN: 1382090 Hom.: 19 Cov.: 33 AF XY: 0.00537 AC XY: 3659 AN XY: 681908

African (AFR) AF: 0.000857 AC: 27 AN: 31512

American (AMR) AF: 0.00292 AC: 104 AN: 35576

Ashkenazi Jewish (ASJ) AF: 0.00128 AC: 32 AN: 25064

East Asian (EAS) AF: 0.00 AC: 0 AN: 35668

South Asian (SAS) AF: 0.00126 AC: 100 AN: 79082

European-Finnish (FIN) AF: 0.00121 AC: 42 AN: 34656

Middle Eastern (MID) AF: 0.000573 AC: 3 AN: 5236

European-Non Finnish (NFE) AF: 0.00650 AC: 7008 AN: 1077562

Other (OTH) AF: 0.00480 AC: 277 AN: 57734

GnomAD4 genome AF: 0.00316 AC: 481 AN: 152326 Hom.: 2 Cov.: 32 AF XY: 0.00277 AC XY: 206 AN XY: 74480

African (AFR) AF: 0.000890 AC: 37 AN: 41580

American (AMR) AF: 0.00261 AC: 40 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4834

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10628

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00550 AC: 374 AN: 68006

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00294 Hom.: 0

Bravo AF: 0.00328

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Autosomal dominant nocturnal frontal lobe epilepsy 3 (2)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy (1)
-	-	1	CHRNB2-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.16
DANN	Benign	0.69
PhyloP100		-5.7
Mutation Taster		=100/0	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

dbSNP: rs55857552; hg19: chr1-154544532;