Genetic Variant CHRNB3:p.Ser403Ser (chr8-42732516-G-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.21

Publications

24 publications found

Variant links:

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]

CHRNB3 links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB3	NM_000749.5 link	c.1209G>C	p.Ser403Ser	synonymous_variant	Exon 5 of 6	ENST00000289957.3	NP_000740.1	Q05901
CHRNB3	NM_001347717.2 link	c.987G>C	p.Ser329Ser	synonymous_variant	Exon 6 of 7		NP_001334646.1
CHRNB3	XM_011544390.3 link	c.822G>C	p.Ser274Ser	synonymous_variant	Exon 3 of 4		XP_011542692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB3	ENST00000289957.3 link	c.1209G>C	p.Ser403Ser	synonymous_variant	Exon 5 of 6	1	NM_000749.5	ENSP00000289957.2		Q05901

Frequencies

GnomAD3 genomes

AF:

0.0447

AC:

6804

AN:

152060

Hom.:

188

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0440

AC XY:

31761

AN XY:

722022

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

2670

5340

8009

10679

13349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1604

3208

4812

6416

8020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0447

AC:

6804

AN:

152178

Hom.:

188

Cov.:

AF XY:

0.0446

AC XY:

3319

AN XY:

74398

show subpopulations

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:

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0383

AC:

2602

AN:

68022

Other (OTH)

AF:

0.0454

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

332

664

995

1327

1659

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0298

Hom.:

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

(source)

DANN

Benign

0.41

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over