Genetic Variant CHRNB3:c.249+9019C>T (chr8-42719453-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000749.5(CHRNB3):c.249+9019C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 152,062 control chromosomes in the GnomAD database, including 46,091 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 0.76 ( 46091 hom., cov: 32)

Consequence

CHRNB3
NM_000749.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.335

Publications

5 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:

ENSG00000255101 (HGNC:):

ENSG00000255101 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.99).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.852 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
CHRNB3	NM_000749.5 link	c.249+9019C>T	intron_variant	Intron 3 of 5	ENST00000289957.3	NP_000740.1
CHRNB3	NM_001347717.2 link	c.27+9019C>T	intron_variant	Intron 4 of 6		NP_001334646.1
CHRNB3	XM_011544390.3 link	c.-139+1839C>T	intron_variant	Intron 1 of 3		XP_011542692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB3	ENST00000289957.3 link	c.249+9019C>T		intron_variant	Intron 3 of 5	1	NM_000749.5	ENSP00000289957.2
ENSG00000255101	ENST00000527318.1 link	n.145+2349G>A		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes

AF:

0.764

AC:

116090

AN:

151942

Hom.:

46076

Cov.:

show subpopulations

Gnomad AFR

AF:

0.534

Gnomad AMI

AF:

0.910

Gnomad AMR

AF:

0.779

Gnomad ASJ

AF:

0.838

Gnomad EAS

AF:

0.869

Gnomad SAS

AF:

0.872

Gnomad FIN

AF:

0.894

Gnomad MID

AF:

0.867

Gnomad NFE

AF:

0.858

Gnomad OTH

AF:

0.760

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.764

AC:

116150

AN:

152062

Hom.:

46091

Cov.:

AF XY:

0.771

AC XY:

57315

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.534

AC:

22096

AN:

41372

American (AMR)

AF:

0.779

AC:

11906

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.838

AC:

2908

AN:

3472

East Asian (EAS)

AF:

0.869

AC:

4502

AN:

5178

South Asian (SAS)

AF:

0.873

AC:

4206

AN:

4820

European-Finnish (FIN)

AF:

0.894

AC:

9489

AN:

10614

Middle Eastern (MID)

AF:

0.857

AC:

252

AN:

294

European-Non Finnish (NFE)

AF:

0.858

AC:

58364

AN:

68018

Other (OTH)

AF:

0.759

AC:

1599

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1274

2547

3821

5094

6368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

852

1704

2556

3408

4260

<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:

0.815

Hom.:

7020

Bravo

AF:

0.741

Asia WGS

AF:

0.816

AC:

2836

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

1.5

(source)

DANN

Benign

0.63

PhyloP100

-0.34

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over