rs767533378

Variant names:

• chr1-154572059-C-T
• rs767533378
• NM_000748.3:c.1236C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000748.3(CHRNB2):​c.1236C>T​(p.Gly412Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000047 in 1,532,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: CHRNB2 NM_000748.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• 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: 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-154572059-C-T is Benign according to our data. Variant chr1-154572059-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 416088.
• BP7: Synonymous conserved (PhyloP=0.031 with no splicing effect.
• BS2: High AC in GnomAd4 at 8 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.1236C>T	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>T	p.Gly412Gly	synonymous	Exon 5 of 6	ENSP00000357461.3	P17787
	CHRNB2	ENST00000637900.1	TSL:5	c.1242C>T	p.Gly414Gly	synonymous	Exon 5 of 6	ENSP00000490474.1	A0A1B0GVD7
	CHRNB2	ENST00000636034.1	TSL:5	n.1236C>T		non_coding_transcript_exon	Exon 5 of 9	ENSP00000489703.1	A0A1B0GTH5

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000369 AC: 47 AN: 127498 AF XY: 0.000330

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.00181

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000504

GnomAD4 exome AF: 0.0000464 AC: 64 AN: 1380380 Hom.: 0 Cov.: 33 AF XY: 0.0000426 AC XY: 29 AN XY: 680950

African (AFR) AF: 0.0000317 AC: 1 AN: 31500

American (AMR) AF: 0.00160 AC: 57 AN: 35552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24874

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 78744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34518

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

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1077092

Other (OTH) AF: 0.0000347 AC: 2 AN: 57636

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74282

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.000523 AC: 8 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000204

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.1
DANN	Benign	0.72
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

Other links and lift over

dbSNP: rs767533378; hg19: chr1-154544535;