rs56095004

Positions:

• chr15-78629898-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000750.5(CHRNB4):​c.407G>A​(p.Arg136Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00792 in 1,610,264 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R136W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0054 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0082 (55 hom.)
• Consequence: CHRNB4 NM_000750.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.244

Genes affected

CHRNB4 (HGNC:1964): (cholinergic receptor nicotinic beta 4 subunit) This gene is found within a conserved gene cluster and encodes one of the beta subunits of the nicotinic acetylcholine receptor (nAChRs) superfamily which form ligand-gated ion channels with a central pore that forms a cation channel. Neuronal nAChRs are pentameric structures that can be either homomeric or heteromeric, with heteromeric structures containing both alpha and beta subunits. Each subunit contains an extracellular amino terminus and four transmembrane domains. Nicotine is one of the agonists that binds to the receptor. Variants in this gene have been associated with nicotine dependence and lung cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2017]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066691935).
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNB4	NM_000750.5	c.407G>A	p.Arg136Gln	missense_variant	5/6	ENST00000261751.8	NP_000741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNB4	ENST00000261751.8	c.407G>A	p.Arg136Gln	missense_variant	5/6	1	NM_000750.5	ENSP00000261751.3
CHRNB4	ENST00000412074.6	c.359+1178G>A		intron_variant		1		ENSP00000416386.2
CHRNB4	ENST00000559849.5	n.*463G>A		non_coding_transcript_exon_variant	12/12	1		ENSP00000457404.1
CHRNB4	ENST00000559849.5	n.*463G>A		3_prime_UTR_variant	12/12	1		ENSP00000457404.1

Frequencies

GnomAD3 genomes AF: 0.00539 AC: 820 AN: 152018 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00996

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00915

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00560 AC: 1384 AN: 247178 Hom.: 7 AF XY: 0.00598 AC XY: 800 AN XY: 133768

Gnomad AFR exome AF: 0.00163

Gnomad AMR exome AF: 0.00209

Gnomad ASJ exome AF: 0.00658

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00805

Gnomad FIN exome AF: 0.00101

Gnomad NFE exome AF: 0.00824

Gnomad OTH exome AF: 0.00513

GnomAD4 exome AF: 0.00818 AC: 11929 AN: 1458128 Hom.: 55 Cov.: 31 AF XY: 0.00812 AC XY: 5889 AN XY: 725248

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00238

Gnomad4 ASJ exome AF: 0.00670

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00785

Gnomad4 FIN exome AF: 0.00170

Gnomad4 NFE exome AF: 0.00939

Gnomad4 OTH exome AF: 0.00676

GnomAD4 genome AF: 0.00539 AC: 820 AN: 152136 Hom.: 5 Cov.: 31 AF XY: 0.00493 AC XY: 367 AN XY: 74384

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00997

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00915

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00773 Hom.: 7

Bravo AF: 0.00526

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00757 AC: 65

ExAC AF: 0.00565 AC: 686

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00840

EpiControl AF: 0.00854

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.6
DANN	Benign	0.94
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.16	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.86	L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.12
Sift	Benign	0.30	T
Sift4G	Benign	0.30	T
Polyphen		0.0010	B
Vest4		0.019
MVP		0.45
MPC		0.35
ClinPred		0.00092	T
GERP RS		0.57
Varity_R		0.037
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs56095004; hg19: chr15-78922240;