1-154572059-C-G

Variant names:

• chr1-154572059-C-G
• NM_000748.3:c.1236C>G
• CHRNB2 p.Gly412Gly

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000748.3(CHRNB2):​c.1236C>G​(p.Gly412Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G412G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000087 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRNB2 NM_000748.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0310
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP7: Synonymous conserved (PhyloP=0.031 with no splicing effect.

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.1236C>G	p.Gly412Gly	synonymous	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.1236C>G	p.Gly412Gly	synonymous	Exon 5 of 6	ENSP00000357461.3	P17787
	CHRNB2	ENST00000637900.1	TSL:5	c.1242C>G	p.Gly414Gly	synonymous	Exon 5 of 6	ENSP00000490474.1	A0A1B0GVD7
	CHRNB2	ENST00000636034.1	TSL:5	n.1236C>G		non_coding_transcript_exon	Exon 5 of 9	ENSP00000489703.1	A0A1B0GTH5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000869 AC: 12 AN: 1380366 Hom.: 0 Cov.: 33 AF XY: 0.00000881 AC XY: 6 AN XY: 680942

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31500

American (AMR) AF: 0.0000281 AC: 1 AN: 35550

Ashkenazi Jewish (ASJ) AF: 0.0000804 AC: 2 AN: 24874

East Asian (EAS) AF: 0.00 AC: 0 AN: 35682

South Asian (SAS) AF: 0.0000254 AC: 2 AN: 78744

European-Finnish (FIN) AF: 0.0000290 AC: 1 AN: 34516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4782

European-Non Finnish (NFE) AF: 0.00000557 AC: 6 AN: 1077082

Other (OTH) AF: 0.00 AC: 0 AN: 57636

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.81
DANN	Benign	0.60
PhyloP100		0.031
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-154544535;