rs4953

Variant names:

• chr8-42732516-G-C
• rs4953
• NM_000749.5:c.1209G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-42732516-G-C
• chr8-42732516-G-A
• chr8-42732516-G-T

Variant summary

Our verdict is Benign. The variant received -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. Variant has been reported in ClinVar as (no stars).

• 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
• Publications: 24 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=-0.88).
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000749.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB3	NM_000749.5	MANE Select	c.1209G>C	p.Ser403Ser	synonymous	Exon 5 of 6	NP_000740.1	Q05901
	CHRNB3	NM_001347717.2		c.987G>C	p.Ser329Ser	synonymous	Exon 6 of 7	NP_001334646.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB3	ENST00000289957.3	TSL:1 MANE Select	c.1209G>C	p.Ser403Ser	synonymous	Exon 5 of 6	ENSP00000289957.2	Q05901

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

GnomAD2 exomes AF: 0.0467 AC: 11182 AN: 239538 AF XY: 0.0500

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 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

African (AFR) AF: 0.0560 AC: 1838 AN: 32808

American (AMR) AF: 0.0267 AC: 1122 AN: 42038

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2623 AN: 25710

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39664

South Asian (SAS) AF: 0.0882 AC: 7394 AN: 83868

European-Finnish (FIN) AF: 0.0466 AC: 2481 AN: 53202

Middle Eastern (MID) AF: 0.106 AC: 607 AN: 5700

European-Non Finnish (NFE) AF: 0.0374 AC: 41503 AN: 1109096

Other (OTH) AF: 0.0498 AC: 2990 AN: 60028

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

African (AFR) AF: 0.0537 AC: 2229 AN: 41504

American (AMR) AF: 0.0325 AC: 496 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 369 AN: 3466

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.0782 AC: 377 AN: 4822

European-Finnish (FIN) AF: 0.0502 AC: 531 AN: 10588

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

European-Non Finnish (NFE) AF: 0.0383 AC: 2602 AN: 68022

Other (OTH) AF: 0.0454 AC: 96 AN: 2114

Alfa AF: 0.0298 Hom.: 31

Bravo AF: 0.0436

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.31
DANN	Benign	0.41
PhyloP100		-1.2
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: rs4953; hg19: chr8-42587659;