1-154572014-G-C

Position:

• chr1-154572014-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000748.3(CHRNB2):​c.1191G>C​(p.Gln397His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,533,948 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0067 (7 hom., cov: 32)
  • Exomes 𝑓: 0.012 (114 hom.)
• Consequence: CHRNB2 NM_000748.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.149

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069208145).
• BP6: Variant 1-154572014-G-C is Benign according to our data. Variant chr1-154572014-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158330.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=6, Uncertain_significance=1}. Variant chr1-154572014-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00665 (1014/152384) while in subpopulation NFE AF= 0.0114 (774/68034). AF 95% confidence interval is 0.0107. There are 7 homozygotes in gnomad4. There are 460 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1014 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNB2	NM_000748.3	c.1191G>C	p.Gln397His	missense_variant	5/6	ENST00000368476.4	NP_000739.1
CHRNB2	XM_017000180.3	c.681G>C	p.Gln227His	missense_variant	2/3		XP_016855669.1
CHRNB2	XR_001736952.3	n.1458G>C		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNB2	ENST00000368476.4	c.1191G>C	p.Gln397His	missense_variant	5/6	1	NM_000748.3	ENSP00000357461	P4
CHRNB2	ENST00000637900.1	c.1197G>C	p.Gln399His	missense_variant	5/6	5		ENSP00000490474	A1
CHRNB2	ENST00000636034.1	c.1191G>C	p.Gln397His	missense_variant, NMD_transcript_variant	5/9	5		ENSP00000489703

Frequencies

GnomAD3 genomes AF: 0.00666 AC: 1014 AN: 152266 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00583 AC: 757 AN: 129764 Hom.: 5 AF XY: 0.00556 AC XY: 395 AN XY: 71032

Gnomad AFR exome AF: 0.00194

Gnomad AMR exome AF: 0.00374

Gnomad ASJ exome AF: 0.000623

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00274

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00673

GnomAD4 exome AF: 0.0120 AC: 16598 AN: 1381564 Hom.: 114 Cov.: 33 AF XY: 0.0117 AC XY: 7948 AN XY: 681480

Gnomad4 AFR exome AF: 0.00213

Gnomad4 AMR exome AF: 0.00377

Gnomad4 ASJ exome AF: 0.000519

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00262

Gnomad4 FIN exome AF: 0.00252

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00665 AC: 1014 AN: 152384 Hom.: 7 Cov.: 32 AF XY: 0.00617 AC XY: 460 AN XY: 74524

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00703 Hom.: 2

Bravo AF: 0.00711

ESP6500AA AF: 0.000644 AC: 2

ESP6500EA AF: 0.00544 AC: 35

ExAC AF: 0.00223 AC: 180

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 14, 2015	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CHRNB2: PP2, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 09, 2017	- -

Autosomal dominant nocturnal frontal lobe epilepsy 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 15, 2014

- -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.54	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.0069	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.36	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.37	N;.
REVEL	Benign	0.25
Sift	Benign	0.24	T;.
Sift4G	Benign	0.28	T;.
Polyphen		0.0	B;.
Vest4		0.31
MutPred		0.13		Gain of catalytic residue at L399 (P = 0.0997);.;
MVP		0.66
MPC		1.0
ClinPred		0.0037	T
GERP RS		2.8
Varity_R		0.11
gMVP		0.69

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: rs55685423; hg19: chr1-154544490; COSMIC: COSV63809188; COSMIC: COSV63809188;