8-27469840-C-A

Variant names:

• chr8-27469840-C-A
• rs201922955
• NM_000742.4:c.215G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000742.4(CHRNA2):​c.215G>T​(p.Arg72Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R72H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHRNA2 NM_000742.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.668
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.215G>T	p.Arg72Leu	missense_variant	Exon 3 of 7	ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3	c.215G>T	p.Arg72Leu	missense_variant	Exon 3 of 7	5	NM_000742.4	ENSP00000385026.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251406 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Uncertain:1

Mar 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 72 of the CHRNA2 protein (p.Arg72Leu). This variant is present in population databases (rs201922955, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CHRNA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 421987). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CHRNA2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Aug 16, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the CHRNA2 gene. The R72L variant hasnot been published as a pathogenic variant, nor has it been reported as a benign variant to ourknowledge. It was not observed in approximately 6,500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant inthese populations. The R72L variant is a non-conservative amino acid substitution, which is likely toimpact secondary protein structure as these residues differ in polarity, charge, size and/or otherproperties. This substitution occurs at a position conserved through mammals and in silico analysispredicts this variant is probably damaging to the protein structure/function. However, missensevariants in nearby residues have not been reported in the Human Gene Mutation Database inassociation with CHRNA2-related disorders (Stenson et al., 2014). Therefore, based on the currentlyavailable information, it is unclear whether this variant is a pathogenic variant or a rare benignvariant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.45	T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.8	L;.;L;.;.
PhyloP100		0.67
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.6	D;.;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D;.;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;.;D
Polyphen		0.89	P;.;.;.;.
Vest4		0.58
MutPred		0.63		Loss of MoRF binding (P = 0.0136);.;Loss of MoRF binding (P = 0.0136);Loss of MoRF binding (P = 0.0136);Loss of MoRF binding (P = 0.0136);
MVP		0.77
MPC		0.80
ClinPred		0.86	D
GERP RS		4.8
Varity_R		0.79
gMVP		0.64
Mutation Taster		=60/40	polymorphism

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: rs201922955; hg19: chr8-27327357;