chr8-42732516-G-C

Position:

• chr8-42732516-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000749.5(CHRNB3):​c.1209G>C​(p.Ser403Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 1,604,292 control chromosomes in the GnomAD database, including 1,842 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 0.045 (188 hom., cov: 33)
  • Exomes 𝑓: 0.042 (1654 hom.)
• Consequence: CHRNB3 NM_000749.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP7: Synonymous conserved (PhyloP=-1.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0717 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNB3	NM_000749.5	c.1209G>C	p.Ser403Ser	synonymous_variant	5/6	ENST00000289957.3	NP_000740.1
CHRNB3	NM_001347717.2	c.987G>C	p.Ser329Ser	synonymous_variant	6/7		NP_001334646.1
CHRNB3	XM_011544390.3	c.822G>C	p.Ser274Ser	synonymous_variant	3/4		XP_011542692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNB3	ENST00000289957.3	c.1209G>C	p.Ser403Ser	synonymous_variant	5/6	1	NM_000749.5	ENSP00000289957.2

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6804 AN: 152060 Hom.: 188 Cov.: 33

Gnomad AFR AF: 0.0536

Gnomad AMI AF: 0.0760

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0785

Gnomad FIN AF: 0.0502

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0383

Gnomad OTH AF: 0.0464

GnomAD3 exomes AF: 0.0467 AC: 11182 AN: 239538 Hom.: 389 AF XY: 0.0500 AC XY: 6491 AN XY: 129888

Gnomad AFR exome AF: 0.0518

Gnomad AMR exome AF: 0.0265

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.000668

Gnomad SAS exome AF: 0.0873

Gnomad FIN exome AF: 0.0482

Gnomad NFE exome AF: 0.0434

Gnomad OTH exome AF: 0.0544

GnomAD4 exome AF: 0.0417 AC: 60572 AN: 1452114 Hom.: 1654 Cov.: 32 AF XY: 0.0440 AC XY: 31761 AN XY: 722022

Gnomad4 AFR exome AF: 0.0560

Gnomad4 AMR exome AF: 0.0267

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0882

Gnomad4 FIN exome AF: 0.0466

Gnomad4 NFE exome AF: 0.0374

Gnomad4 OTH exome AF: 0.0498

GnomAD4 genome AF: 0.0447 AC: 6804 AN: 152178 Hom.: 188 Cov.: 33 AF XY: 0.0446 AC XY: 3319 AN XY: 74398

Gnomad4 AFR AF: 0.0537

Gnomad4 AMR AF: 0.0325

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0782

Gnomad4 FIN AF: 0.0502

Gnomad4 NFE AF: 0.0383

Gnomad4 OTH AF: 0.0454

Alfa AF: 0.0298 Hom.: 31

Bravo AF: 0.0436

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.31
DANN	Benign	0.41

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: rs4953; hg19: chr8-42587659;