chr15-78629898-C-G

Variant names:

• chr15-78629898-C-G
• rs56095004
• NM_000750.5:c.407G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000750.5(CHRNB4):​c.407G>C​(p.Arg136Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CHRNB4 NM_000750.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.244
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32588512).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000750.5. 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
	CHRNB4	NM_000750.5	MANE Select	c.407G>C	p.Arg136Pro	missense	Exon 5 of 6	NP_000741.1
	CHRNB4	NM_001256567.3		c.359+1178G>C		intron	N/A	NP_001243496.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB4	ENST00000261751.8	TSL:1 MANE Select	c.407G>C	p.Arg136Pro	missense	Exon 5 of 6	ENSP00000261751.3
	CHRNB4	ENST00000559849.5	TSL:1	n.*463G>C		non_coding_transcript_exon	Exon 12 of 12	ENSP00000457404.1
	CHRNB4	ENST00000559849.5	TSL:1	n.*463G>C		3_prime_UTR	Exon 12 of 12	ENSP00000457404.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458134 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725252

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25974

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 85984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111250

Other (OTH) AF: 0.00 AC: 0 AN: 60338

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	0.0013	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	7.4
DANN	Benign	0.92
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.24
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.46
Sift	Benign	0.14	T
Sift4G	Benign	0.17	T
Polyphen		0.40	B
Vest4		0.33
MutPred		0.41		Gain of glycosylation at S137 (P = 0.0557)
MVP		0.73
MPC		1.0
ClinPred		0.18	T
GERP RS		0.57
Varity_R		0.66
gMVP		0.79

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

Other links and lift over

dbSNP: rs56095004; hg19: chr15-78922240;