rs4952

Variant names:

• chr8-42731922-C-T
• rs4952
• NM_000749.5:c.615C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The ENST00000289957.3(CHRNB3):​c.615C>T​(p.Asn205Asn) 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 ENST00000289957.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0230
• Publications: 26 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000289957.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB3	NM_000749.5	MANE Select	c.615C>T	p.Asn205Asn	synonymous	Exon 5 of 6	NP_000740.1
	CHRNB3	NM_001347717.2		c.393C>T	p.Asn131Asn	synonymous	Exon 6 of 7	NP_001334646.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB3	ENST00000289957.3	TSL:1 MANE Select	c.615C>T	p.Asn205Asn	synonymous	Exon 5 of 6	ENSP00000289957.2

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

GnomAD2 exomes AF: 0.0435 AC: 10931 AN: 251458 AF XY: 0.0478

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 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

African (AFR) AF: 0.0113 AC: 378 AN: 33480

American (AMR) AF: 0.0246 AC: 1100 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2664 AN: 26134

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.0878 AC: 7570 AN: 86254

European-Finnish (FIN) AF: 0.0466 AC: 2492 AN: 53420

Middle Eastern (MID) AF: 0.106 AC: 614 AN: 5768

European-Non Finnish (NFE) AF: 0.0374 AC: 41583 AN: 1111990

Other (OTH) AF: 0.0468 AC: 2827 AN: 60396

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

African (AFR) AF: 0.00918 AC: 381 AN: 41504

American (AMR) AF: 0.0293 AC: 447 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 370 AN: 3468

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.0785 AC: 378 AN: 4818

European-Finnish (FIN) AF: 0.0499 AC: 528 AN: 10580

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0382 AC: 2595 AN: 68016

Other (OTH) AF: 0.0360 AC: 76 AN: 2112

Alfa AF: 0.0387 Hom.: 385

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.20
DANN	Benign	0.66
PhyloP100		-0.023
Mutation Taster		=100/0	polymorphism (auto)

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: rs4952; hg19: chr8-42587065;