chr15-78629887-T-C

Position:

• chr15-78629887-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000750.5(CHRNB4):​c.418A>G​(p.Ser140Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00967 in 1,612,488 control chromosomes in the GnomAD database, including 277 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.020 (64 hom., cov: 31)
  • Exomes 𝑓: 0.0086 (213 hom.)
• Consequence: CHRNB4 NM_000750.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.09

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008622795).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.079 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNB4	NM_000750.5	c.418A>G	p.Ser140Gly	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.418A>G	p.Ser140Gly	missense_variant	5/6	1	NM_000750.5	ENSP00000261751	P1
CHRNB4	ENST00000412074.6	c.359+1189A>G		intron_variant		1		ENSP00000416386
CHRNB4	ENST00000559849.5	c.*474A>G		3_prime_UTR_variant, NMD_transcript_variant	12/12	1		ENSP00000457404

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3053 AN: 152122 Hom.: 64 Cov.: 31

Gnomad AFR AF: 0.0464

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.0852

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00576

Gnomad OTH AF: 0.0282

GnomAD3 exomes AF: 0.0146 AC: 3635 AN: 249476 Hom.: 99 AF XY: 0.0137 AC XY: 1846 AN XY: 134874

Gnomad AFR exome AF: 0.0466

Gnomad AMR exome AF: 0.00819

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.0801

Gnomad SAS exome AF: 0.00874

Gnomad FIN exome AF: 0.00488

Gnomad NFE exome AF: 0.00591

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.00858 AC: 12536 AN: 1460248 Hom.: 213 Cov.: 31 AF XY: 0.00845 AC XY: 6138 AN XY: 726402

Gnomad4 AFR exome AF: 0.0461

Gnomad4 AMR exome AF: 0.00819

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.0736

Gnomad4 SAS exome AF: 0.00845

Gnomad4 FIN exome AF: 0.00456

Gnomad4 NFE exome AF: 0.00515

Gnomad4 OTH exome AF: 0.0148

GnomAD4 genome AF: 0.0201 AC: 3060 AN: 152240 Hom.: 64 Cov.: 31 AF XY: 0.0205 AC XY: 1529 AN XY: 74440

Gnomad4 AFR AF: 0.0465

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.0856

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.00442

Gnomad4 NFE AF: 0.00576

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.00998 Hom.: 48

Bravo AF: 0.0219

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.0446 AC: 196

ESP6500EA AF: 0.00641 AC: 55

ExAC AF: 0.0152 AC: 1844

Asia WGS AF: 0.0360 AC: 124 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.32
Sift	Benign	0.24	T
Sift4G	Benign	0.32	T
Polyphen		0.95	P
Vest4		0.23
MPC		0.89
ClinPred		0.042	T
GERP RS		5.0
Varity_R		0.53
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs56218866; hg19: chr15-78922229; COSMIC: COSV55715250; COSMIC: COSV55715250;