rs61737499

chr15-78629181-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000750.5(CHRNB4):c.1124C>T(p.Thr375Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000871 in 1,614,010 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (4 hom.)
• Consequence: CHRNB4 NM_000750.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.05

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057582557).
• BP6: Variant 15-78629181-G-A is Benign according to our data. Variant chr15-78629181-G-A is described in ClinVar as [Benign]. Clinvar id is 779904.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00049 (716/1461774) while in subpopulation AFR AF= 0.0165 (551/33480). AF 95% confidence interval is 0.0153. There are 4 homozygotes in gnomad4_exome. There are 304 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB4	NM_000750.5	c.1124C>T	p.Thr375Ile	missense_variant	5/6	ENST00000261751.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB4	ENST00000261751.8	c.1124C>T	p.Thr375Ile	missense_variant	5/6	1	NM_000750.5	P1
CHRNB4	ENST00000412074.6	c.359+1895C>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00450 AC: 684 AN: 152118 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00122 AC: 307 AN: 251032 Hom.: 3 AF XY: 0.000788 AC XY: 107 AN XY: 135734

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000490 AC: 716 AN: 1461774 Hom.: 4 Cov.: 31 AF XY: 0.000418 AC XY: 304 AN XY: 727174

Gnomad4 AFR exome AF: 0.0165

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00453 AC: 689 AN: 152236 Hom.: 11 Cov.: 32 AF XY: 0.00437 AC XY: 325 AN XY: 74432

Gnomad4 AFR AF: 0.0157

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.000929 Hom.: 1

Bravo AF: 0.00518

ESP6500AA AF: 0.0164 AC: 72

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00152 AC: 185

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	9.0
Dann	Benign	0.66
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.083
Sift	Benign	0.26	T
Sift4G	Benign	0.23	T
Polyphen		0.21	B
Vest4		0.24
MVP		0.79
MPC		0.33
ClinPred		0.0072	T
GERP RS		2.9
Varity_R		0.052
gMVP		0.19

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: rs61737499; hg19: chr15-78921523;