1-154571362-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_000748.3(CHRNB2):​c.539G>T​(p.Arg180Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R180C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CHRNB2
NM_000748.3 missense

Scores

2
12
5

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 3.24
Variant links:
Genes affected
CHRNB2 (HGNC:1962): (cholinergic receptor nicotinic beta 2 subunit) Neuronal acetylcholine receptors are homo- or heteropentameric complexes composed of homologous alpha and beta subunits. They belong to a superfamily of ligand-gated ion channels which allow the flow of sodium and potassium across the plasma membrane in response to ligands such as acetylcholine and nicotine. This gene encodes one of several beta subunits. Mutations in this gene are associated with autosomal dominant nocturnal frontal lobe epilepsy. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.785
BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHRNB2NM_000748.3 linkc.539G>T p.Arg180Leu missense_variant Exon 5 of 6 ENST00000368476.4 NP_000739.1 P17787Q5SXY3
CHRNB2XM_017000180.3 linkc.29G>T p.Arg10Leu missense_variant Exon 2 of 3 XP_016855669.1
CHRNB2XR_001736952.3 linkn.806G>T non_coding_transcript_exon_variant Exon 5 of 7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHRNB2ENST00000368476.4 linkc.539G>T p.Arg180Leu missense_variant Exon 5 of 6 1 NM_000748.3 ENSP00000357461.3 P17787
CHRNB2ENST00000637900.1 linkc.545G>T p.Arg182Leu missense_variant Exon 5 of 6 5 ENSP00000490474.1 A0A1B0GVD7
CHRNB2ENST00000636034.1 linkn.539G>T non_coding_transcript_exon_variant Exon 5 of 9 5 ENSP00000489703.1 A0A1B0GTH5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461884
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
2
AN XY:
727244
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:
0.00000540
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

CHRNB2-related disorder Uncertain:1
Nov 20, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The CHRNB2 c.539G>T variant is predicted to result in the amino acid substitution p.Arg180Leu. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.54
BayesDel_addAF
Uncertain
0.055
T
BayesDel_noAF
Benign
-0.16
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D;.
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Benign
0.070
D
MetaRNN
Pathogenic
0.78
D;D
MetaSVM
Benign
-0.43
T
MutationAssessor
Benign
1.6
L;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-3.5
D;.
REVEL
Pathogenic
0.67
Sift
Uncertain
0.016
D;.
Sift4G
Uncertain
0.058
T;.
Polyphen
0.95
P;.
Vest4
0.75
MutPred
0.69
Loss of phosphorylation at T177 (P = 0.0727);.;
MVP
0.77
MPC
2.1
ClinPred
0.97
D
GERP RS
3.5
Varity_R
0.53
gMVP
0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-154543838; API