8-27467305-T-C

Variant names:

• chr8-27467305-T-C
• rs891398
• NM_000742.4:c.373A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000742.4(CHRNA2):​c.373A>G​(p.Thr125Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,609,834 control chromosomes in the GnomAD database, including 212,156 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. T125T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.58 (26939 hom., cov: 33)
  • Exomes 𝑓: 0.50 (185217 hom.)
• Consequence: CHRNA2 NM_000742.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.868
• Publications: 58 publications found

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]

CHRNA2 Gene-Disease associations (from GenCC):

• autosomal dominant nocturnal frontal lobe epilepsy 4

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae)
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sleep-related hypermotor epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• benign familial infantile epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8624587E-6).
• BP6: Variant 8-27467305-T-C is Benign according to our data. Variant chr8-27467305-T-C is described in ClinVar as Benign. ClinVar VariationId is 128739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000742.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA2	NM_000742.4	MANE Select	c.373A>G	p.Thr125Ala	missense	Exon 5 of 7	NP_000733.2
	CHRNA2	NM_001282455.2		c.328A>G	p.Thr110Ala	missense	Exon 5 of 7	NP_001269384.1
	CHRNA2	NM_001347705.2		c.-100A>G		5_prime_UTR	Exon 5 of 7	NP_001334634.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA2	ENST00000407991.3	TSL:5 MANE Select	c.373A>G	p.Thr125Ala	missense	Exon 5 of 7	ENSP00000385026.1
	CHRNA2	ENST00000520600.1	TSL:1	n.213A>G		non_coding_transcript_exon	Exon 1 of 2
	CHRNA2	ENST00000523695.5	TSL:1	n.373A>G		non_coding_transcript_exon	Exon 5 of 7	ENSP00000430612.1

Frequencies

GnomAD3 genomes AF: 0.581 AC: 88351 AN: 152006 Hom.: 26890 Cov.: 33

Gnomad AFR AF: 0.765

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.526

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.559

GnomAD2 exomes AF: 0.529 AC: 133044 AN: 251418 AF XY: 0.516

Gnomad AFR exome AF: 0.775

Gnomad AMR exome AF: 0.591

Gnomad ASJ exome AF: 0.515

Gnomad EAS exome AF: 0.644

Gnomad FIN exome AF: 0.525

Gnomad NFE exome AF: 0.495

Gnomad OTH exome AF: 0.514

GnomAD4 exome AF: 0.498 AC: 726432 AN: 1457710 Hom.: 185217 Cov.: 40 AF XY: 0.495 AC XY: 359210 AN XY: 725488

African (AFR) AF: 0.779 AC: 26013 AN: 33396

American (AMR) AF: 0.585 AC: 26143 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 13552 AN: 26114

East Asian (EAS) AF: 0.687 AC: 27238 AN: 39672

South Asian (SAS) AF: 0.396 AC: 34136 AN: 86168

European-Finnish (FIN) AF: 0.524 AC: 27971 AN: 53402

Middle Eastern (MID) AF: 0.478 AC: 2749 AN: 5756

European-Non Finnish (NFE) AF: 0.486 AC: 538106 AN: 1108244

Other (OTH) AF: 0.507 AC: 30524 AN: 60254

GnomAD4 genome AF: 0.581 AC: 88454 AN: 152124 Hom.: 26939 Cov.: 33 AF XY: 0.582 AC XY: 43260 AN XY: 74382

African (AFR) AF: 0.766 AC: 31774 AN: 41500

American (AMR) AF: 0.582 AC: 8905 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 1825 AN: 3470

East Asian (EAS) AF: 0.646 AC: 3331 AN: 5156

South Asian (SAS) AF: 0.419 AC: 2022 AN: 4830

European-Finnish (FIN) AF: 0.523 AC: 5540 AN: 10584

Middle Eastern (MID) AF: 0.527 AC: 154 AN: 292

European-Non Finnish (NFE) AF: 0.491 AC: 33408 AN: 67976

Other (OTH) AF: 0.553 AC: 1166 AN: 2108

Alfa AF: 0.520 Hom.: 101137

Bravo AF: 0.593

TwinsUK AF: 0.486 AC: 1802

ALSPAC AF: 0.468 AC: 1805

ESP6500AA AF: 0.762 AC: 3356

ESP6500EA AF: 0.487 AC: 4189

ExAC AF: 0.531 AC: 64459

Asia WGS AF: 0.518 AC: 1802 AN: 3478

EpiCase AF: 0.487

EpiControl AF: 0.490

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Jan 02, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 80% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 74. Only high quality variants are reported.

Jun 25, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Autosomal dominant nocturnal frontal lobe epilepsy 4 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Jan 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.27
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0000019	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.1	N
PhyloP100		0.87
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.13
Sift	Benign	0.81	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.036
MPC		0.18
ClinPred		0.0034	T
GERP RS		3.5
Varity_R		0.072
gMVP		0.19
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs891398; hg19: chr8-27324822; COSMIC: COSV107269654; COSMIC: COSV107269654;