rs2472553

chr8-27470994-G-Achr8-27470994-G-Cchr8-27470994-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000742.4(CHRNA2):c.65C>T(p.Thr22Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,613,474 control chromosomes in the GnomAD database, including 19,915 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2187 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17728 hom.)
• Consequence: CHRNA2 NM_000742.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.296

Genes affected

CHRNA2 (HGNC:1956): (cholinergic receptor nicotinic alpha 2 subunit) Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels formed by a pentameric arrangement of alpha and beta subunits to create distinct muscle and neuronal receptors. Neuronal receptors are found throughout the peripheral and central nervous system where they are involved in fast synaptic transmission. This gene encodes an alpha subunit that is widely expressed in the brain. The proposed structure for nAChR subunits is a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region. Mutations in this gene cause autosomal dominant nocturnal frontal lobe epilepsy type 4. Single nucleotide polymorphisms (SNPs) in this gene have been associated with nicotine dependence. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002926439).
• BP6: Variant 8-27470994-G-A is Benign according to our data. Variant chr8-27470994-G-A is described in ClinVar as [Benign]. Clinvar id is 128740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA2	NM_000742.4	c.65C>T	p.Thr22Ile	missense_variant	2/7	ENST00000407991.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA2	ENST00000407991.3	c.65C>T	p.Thr22Ile	missense_variant	2/7	5	NM_000742.4	P2

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24048 AN: 152064 Hom.: 2183 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.166 AC: 41628 AN: 250562 Hom.: 4435 AF XY: 0.160 AC XY: 21720 AN XY: 135500

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.0655

Gnomad EAS exome AF: 0.450

Gnomad SAS exome AF: 0.127

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.145 AC: 211462 AN: 1461292 Hom.: 17728 Cov.: 32 AF XY: 0.144 AC XY: 104428 AN XY: 726976

Gnomad4 AFR exome AF: 0.170

Gnomad4 AMR exome AF: 0.191

Gnomad4 ASJ exome AF: 0.0654

Gnomad4 EAS exome AF: 0.444

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.158 AC: 24080 AN: 152182 Hom.: 2187 Cov.: 32 AF XY: 0.162 AC XY: 12038 AN XY: 74400

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.180

Gnomad4 ASJ AF: 0.0550

Gnomad4 EAS AF: 0.439

Gnomad4 SAS AF: 0.149

Gnomad4 FIN AF: 0.164

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.132

Alfa AF: 0.136 Hom.: 4049

Bravo AF: 0.160

TwinsUK AF: 0.138 AC: 513

ALSPAC AF: 0.130 AC: 501

ESP6500AA AF: 0.184 AC: 810

ESP6500EA AF: 0.131 AC: 1125

ExAC AF: 0.165 AC: 19975

Asia WGS AF: 0.262 AC: 909 AN: 3478

EpiCase AF: 0.125

EpiControl AF: 0.121

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2013	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, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 07, 2016	- -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

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. -

Autosomal dominant nocturnal frontal lobe epilepsy 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	6.2
Dann	Benign	0.061
DEOGEN2	Benign	0.090	T;.;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0096	N
LIST_S2	Benign	0.41	T;T;T;T;T
MetaRNN	Benign	0.0029	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N;N;.;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.23	N;N;N;N;N
REVEL	Benign	0.078
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	0.89	T;T;.;T;.
Polyphen		0.0	B;.;.;.;.
Vest4		0.011
MPC		0.19
ClinPred		0.00054	T
GERP RS		-2.5
Varity_R		0.028
gMVP		0.28

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: rs2472553; hg19: chr8-27328511; COSMIC: COSV53556702; COSMIC: COSV53556702;