15-78625231-T-G

Position:

• chr15-78625231-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000750.5(CHRNB4):​c.1399A>C​(p.Met467Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,434,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. M467V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHRNB4 NM_000750.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.75

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.110275716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNB4	NM_000750.5	c.1399A>C	p.Met467Leu	missense_variant	6/6	ENST00000261751.8	NP_000741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNB4	ENST00000261751.8	c.1399A>C	p.Met467Leu	missense_variant	6/6	1	NM_000750.5	ENSP00000261751	P1
CHRNB4	ENST00000412074.6	c.420A>C	p.Ser140=	synonymous_variant	5/5	1		ENSP00000416386

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1434292 Hom.: 0 Cov.: 34 AF XY: 0.00000141 AC XY: 1 AN XY: 711658

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.58	N
REVEL	Benign	0.21
Sift	Benign	0.51	T
Sift4G	Benign	0.63	T
Polyphen		0.0010	B
Vest4		0.19
MutPred		0.53		Loss of catalytic residue at M467 (P = 3e-04);
MVP		0.53
MPC		0.28
ClinPred		0.81	D
GERP RS		3.5
Varity_R		0.096
gMVP		0.35

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

LitVar

Other links and lift over

dbSNP: rs61737502; hg19: chr15-78917573;