8-42736592-A-G

Variant names:

• chr8-42736592-A-G
• rs35327613
• NM_000749.5:c.1351A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000749.5(CHRNB3):​c.1351A>G​(p.Lys451Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,614,174 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (46 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (39 hom.)
• Consequence: CHRNB3 NM_000749.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.85
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002520442).
• BP6: Variant 8-42736592-A-G is Benign according to our data. Variant chr8-42736592-A-G is described in ClinVar as Benign. ClinVar VariationId is 712805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0142 (2156/152292) while in subpopulation AFR AF = 0.0488 (2028/41558). AF 95% confidence interval is 0.047. There are 46 homozygotes in GnomAd4. There are 992 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB3	NM_000749.5	MANE Select	c.1351A>G	p.Lys451Glu	missense	Exon 6 of 6	NP_000740.1
	CHRNB3	NM_001347717.2		c.1129A>G	p.Lys377Glu	missense	Exon 7 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.1351A>G	p.Lys451Glu	missense	Exon 6 of 6	ENSP00000289957.2

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2151 AN: 152174 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00379 AC: 953 AN: 251470 AF XY: 0.00289

Gnomad AFR exome AF: 0.0519

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00133 AC: 1941 AN: 1461882 Hom.: 39 Cov.: 31 AF XY: 0.00119 AC XY: 868 AN XY: 727244

African (AFR) AF: 0.0459 AC: 1537 AN: 33474

American (AMR) AF: 0.00309 AC: 138 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000558 AC: 62 AN: 1112010

Other (OTH) AF: 0.00315 AC: 190 AN: 60396

GnomAD4 genome AF: 0.0142 AC: 2156 AN: 152292 Hom.: 46 Cov.: 32 AF XY: 0.0133 AC XY: 992 AN XY: 74466

African (AFR) AF: 0.0488 AC: 2028 AN: 41558

American (AMR) AF: 0.00673 AC: 103 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68024

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00607 Hom.: 35

Bravo AF: 0.0168

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0463 AC: 204

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00496 AC: 602

Asia WGS AF: 0.00173 AC: 6 AN: 3474

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.0089
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.49	N
PhyloP100		1.8
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.065
Sift	Benign	0.21	T
Sift4G	Benign	0.98	T
Polyphen		0.24	B
Vest4		0.24
MVP		0.69
MPC		0.35
ClinPred		0.014	T
GERP RS		4.0
Varity_R		0.11
gMVP		0.61
Mutation Taster		=84/16	polymorphism

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: rs35327613; hg19: chr8-42591735;