rs4952

Positions:

• chr8-42731922-C-T

Variant summary

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

The NM_000749.5(CHRNB3):​c.615C>T​(p.Asn205=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,614,024 control chromosomes in the GnomAD database, including 1,728 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 0.032 (122 hom., cov: 33)
  • Exomes 𝑓: 0.041 (1606 hom.)
• Consequence: CHRNB3 NM_000749.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0230

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=-0.77).
• BP7: Synonymous conserved (PhyloP=-0.023 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB3	NM_000749.5	c.615C>T	p.Asn205=	synonymous_variant	5/6	ENST00000289957.3
CHRNB3	NM_001347717.2	c.393C>T	p.Asn131=	synonymous_variant	6/7
CHRNB3	XM_011544390.3	c.228C>T	p.Asn76=	synonymous_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB3	ENST00000289957.3	c.615C>T	p.Asn205=	synonymous_variant	5/6	1	NM_000749.5	P1

Frequencies

GnomAD3 genomes AF: 0.0321 AC: 4888 AN: 152040 Hom.: 122 Cov.: 33

Gnomad AFR AF: 0.00921

Gnomad AMI AF: 0.0738

Gnomad AMR AF: 0.0293

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0786

Gnomad FIN AF: 0.0499

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0382

Gnomad OTH AF: 0.0368

GnomAD3 exomes AF: 0.0435 AC: 10931 AN: 251458 Hom.: 390 AF XY: 0.0478 AC XY: 6491 AN XY: 135904

Gnomad AFR exome AF: 0.00954

Gnomad AMR exome AF: 0.0247

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.000652

Gnomad SAS exome AF: 0.0857

Gnomad FIN exome AF: 0.0480

Gnomad NFE exome AF: 0.0430

Gnomad OTH exome AF: 0.0544

GnomAD4 exome AF: 0.0405 AC: 59242 AN: 1461866 Hom.: 1606 Cov.: 32 AF XY: 0.0430 AC XY: 31279 AN XY: 727242

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.0246

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0878

Gnomad4 FIN exome AF: 0.0466

Gnomad4 NFE exome AF: 0.0374

Gnomad4 OTH exome AF: 0.0468

GnomAD4 genome AF: 0.0321 AC: 4877 AN: 152158 Hom.: 122 Cov.: 33 AF XY: 0.0323 AC XY: 2405 AN XY: 74386

Gnomad4 AFR AF: 0.00918

Gnomad4 AMR AF: 0.0293

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0785

Gnomad4 FIN AF: 0.0499

Gnomad4 NFE AF: 0.0382

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0416 Hom.: 210

Bravo AF: 0.0294

Asia WGS AF: 0.0310 AC: 107 AN: 3478

EpiCase AF: 0.0483

EpiControl AF: 0.0478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.20
DANN	Benign	0.66

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: rs4952; hg19: chr8-42587065;