rs4954

chr8-42732653-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000749.5(CHRNB3):c.1242+104G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.931 in 1,053,734 control chromosomes in the GnomAD database, including 458,169 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.90 (61451 hom., cov: 33)
  • Exomes 𝑓: 0.94 (396718 hom.)
• Consequence: CHRNB3 NM_000749.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.957

Genes affected

CHRNB3 (HGNC:1963): (cholinergic receptor nicotinic beta 3 subunit) The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The nAChRs are (hetero)pentamers composed of homologous subunits. The subunits that make up the muscle and neuronal forms of nAChRs are encoded by separate genes and have different primary structure. There are several subtypes of neuronal nAChRs that vary based on which homologous subunits are arranged around the central channel. They are classified as alpha-subunits if, like muscle alpha-1 (MIM 100690), they have a pair of adjacent cysteines as part of the presumed acetylcholine binding site. Subunits lacking these cysteine residues are classified as beta-subunits (Groot Kormelink and Luyten, 1997 [PubMed 9009220]). Elliott et al. (1996) [PubMed 8906617] stated that the proposed structure for each subunit is a conserved N-terminal extracellular domain followed by 3 conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region.[supplied by OMIM, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.945 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB3	NM_000749.5	c.1242+104G>A		intron_variant		ENST00000289957.3
CHRNB3	NM_001347717.2	c.1020+104G>A		intron_variant
CHRNB3	XM_011544390.3	c.855+104G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB3	ENST00000289957.3	c.1242+104G>A		intron_variant		1	NM_000749.5	P1

Frequencies

GnomAD3 genomes AF: 0.896 AC: 136220 AN: 152084 Hom.: 61416 Cov.: 33

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.958

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.914

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.908

Gnomad FIN AF: 0.939

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.951

Gnomad OTH AF: 0.896

GnomAD4 exome AF: 0.937 AC: 845117 AN: 901532 Hom.: 396718 AF XY: 0.937 AC XY: 423330 AN XY: 451726

Gnomad4 AFR exome AF: 0.786

Gnomad4 AMR exome AF: 0.865

Gnomad4 ASJ exome AF: 0.912

Gnomad4 EAS exome AF: 0.893

Gnomad4 SAS exome AF: 0.913

Gnomad4 FIN exome AF: 0.934

Gnomad4 NFE exome AF: 0.950

Gnomad4 OTH exome AF: 0.922

GnomAD4 genome AF: 0.896 AC: 136302 AN: 152202 Hom.: 61451 Cov.: 33 AF XY: 0.895 AC XY: 66618 AN XY: 74418

Gnomad4 AFR AF: 0.798

Gnomad4 AMR AF: 0.883

Gnomad4 ASJ AF: 0.914

Gnomad4 EAS AF: 0.858

Gnomad4 SAS AF: 0.909

Gnomad4 FIN AF: 0.939

Gnomad4 NFE AF: 0.951

Gnomad4 OTH AF: 0.894

Alfa AF: 0.931 Hom.: 13402

Bravo AF: 0.884

Asia WGS AF: 0.846 AC: 2941 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.35
Dann	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs4954; hg19: chr8-42587796; COSMIC: COSV51493958;