NM_000750.5:c.272C>T

Variant names:

• chr15-78631163-G-A
• rs12914008
• NM_000750.5:c.272C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000750.5(CHRNB4):​c.272C>T​(p.Thr91Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 1,614,048 control chromosomes in the GnomAD database, including 1,340 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.025 (70 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1270 hom.)
• Consequence: CHRNB4 NM_000750.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.38
• Publications: 48 publications found

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]

CHRNB4 Gene-Disease associations (from GenCC):

• lung cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000259555 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.013037175).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0251 (3817/152308) while in subpopulation NFE AF = 0.0419 (2848/68016). AF 95% confidence interval is 0.0406. There are 70 homozygotes in GnomAd4. There are 1785 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3817 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB4	NM_000750.5	c.272C>T	p.Thr91Ile	missense_variant	Exon 4 of 6	ENST00000261751.8	NP_000741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB4	ENST00000261751.8	c.272C>T	p.Thr91Ile	missense_variant	Exon 4 of 6	1	NM_000750.5	ENSP00000261751.3

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3817 AN: 152190 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.00758

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.0238

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0419

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0241 AC: 6058 AN: 251476 AF XY: 0.0246

Gnomad AFR exome AF: 0.00621

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0163

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0267

Gnomad NFE exome AF: 0.0394

Gnomad OTH exome AF: 0.0257

GnomAD4 exome AF: 0.0385 AC: 56345 AN: 1461740 Hom.: 1270 Cov.: 32 AF XY: 0.0375 AC XY: 27243 AN XY: 727176

African (AFR) AF: 0.00633 AC: 212 AN: 33480

American (AMR) AF: 0.0105 AC: 471 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 397 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00794 AC: 685 AN: 86256

European-Finnish (FIN) AF: 0.0258 AC: 1376 AN: 53418

Middle Eastern (MID) AF: 0.00867 AC: 50 AN: 5768

European-Non Finnish (NFE) AF: 0.0462 AC: 51316 AN: 1111866

Other (OTH) AF: 0.0304 AC: 1836 AN: 60392

GnomAD4 genome AF: 0.0251 AC: 3817 AN: 152308 Hom.: 70 Cov.: 32 AF XY: 0.0240 AC XY: 1785 AN XY: 74464

African (AFR) AF: 0.00755 AC: 314 AN: 41572

American (AMR) AF: 0.0164 AC: 251 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4828

European-Finnish (FIN) AF: 0.0238 AC: 253 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0419 AC: 2848 AN: 68016

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0356 Hom.: 404

Bravo AF: 0.0244

TwinsUK AF: 0.0477 AC: 177

ALSPAC AF: 0.0511 AC: 197

ESP6500AA AF: 0.00751 AC: 33

ESP6500EA AF: 0.0440 AC: 378

ExAC AF: 0.0238 AC: 2892

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0379

EpiControl AF: 0.0366

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.6	L;L
PhyloP100		3.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.27
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.014	D;T
Vest4		0.081
ClinPred		0.017	T
GERP RS		4.3
Varity_R		0.25
gMVP		0.37
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs12914008; hg19: chr15-78923505; COSMIC: COSV55715744; COSMIC: COSV55715744;