rs56095004

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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. 12/21 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: not found (cov: 31)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

CHRNB4
NM_000750.5 missense

Scores

1
4
14

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.244
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHRNB4NM_000750.5 linkc.407G>C p.Arg136Pro missense_variant Exon 5 of 6 ENST00000261751.8 NP_000741.1 P30926-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHRNB4ENST00000261751.8 linkc.407G>C p.Arg136Pro missense_variant Exon 5 of 6 1 NM_000750.5 ENSP00000261751.3 P30926-1
CHRNB4ENST00000412074.6 linkc.359+1178G>C intron_variant Intron 4 of 4 1 ENSP00000416386.2 P30926-2
CHRNB4ENST00000559849.5 linkn.*463G>C non_coding_transcript_exon_variant Exon 12 of 12 1 ENSP00000457404.1 H3BU02
CHRNB4ENST00000559849.5 linkn.*463G>C 3_prime_UTR_variant Exon 12 of 12 1 ENSP00000457404.1 H3BU02

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
show subpopulations
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:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-78922240; API