rs17621256

Positions:

• chr8-42734765-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000749.5(CHRNB3):​c.1243-1719C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 152,122 control chromosomes in the GnomAD database, including 46 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 0.020 (46 hom., cov: 30)
• Consequence: CHRNB3 NM_000749.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.54

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=-0.91).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0196 (2987/152122) while in subpopulation NFE AF= 0.0309 (2098/67996). AF 95% confidence interval is 0.0298. There are 46 homozygotes in gnomad4. There are 1413 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB3	NM_000749.5	c.1243-1719C>A		intron_variant		ENST00000289957.3
CHRNB3	NM_001347717.2	c.1021-1719C>A		intron_variant
CHRNB3	XM_011544390.3	c.856-1719C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB3	ENST00000289957.3	c.1243-1719C>A		intron_variant		1	NM_000749.5	P1

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2982 AN: 152006 Hom.: 46 Cov.: 30

Gnomad AFR AF: 0.00491

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.0220

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0309

Gnomad OTH AF: 0.0144

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0196 AC: 2987 AN: 152122 Hom.: 46 Cov.: 30 AF XY: 0.0190 AC XY: 1413 AN XY: 74344

Gnomad4 AFR AF: 0.00489

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0263

Gnomad4 FIN AF: 0.0220

Gnomad4 NFE AF: 0.0309

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0254 Hom.: 11

Bravo AF: 0.0173

Asia WGS AF: 0.00875 AC: 30 AN: 3444

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.13
DANN	Benign	0.61

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: rs17621256; hg19: chr8-42589908;