rs56298562

Variant names:

• chr8-27463119-G-A
• rs56298562
• NM_000742.4:c.1324C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000742.4(CHRNA2):​c.1324C>T​(p.Leu442Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,608,776 control chromosomes in the GnomAD database, including 678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (46 hom., cov: 33)
  • Exomes 𝑓: 0.026 (632 hom.)
• Consequence: CHRNA2 NM_000742.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.05

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 8-27463119-G-A is Benign according to our data. Variant chr8-27463119-G-A is described in ClinVar as [Benign]. Clinvar id is 128737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-27463119-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0178 (2710/152350) while in subpopulation SAS AF= 0.03 (145/4830). AF 95% confidence interval is 0.026. There are 46 homozygotes in gnomad4. There are 1377 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2710 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.1324C>T	p.Leu442Leu	synonymous_variant	Exon 6 of 7	ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3	c.1324C>T	p.Leu442Leu	synonymous_variant	Exon 6 of 7	5	NM_000742.4	ENSP00000385026.1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2713 AN: 152232 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.00374

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0302

Gnomad FIN AF: 0.0370

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0244

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0224 AC: 5608 AN: 250796 Hom.: 100 AF XY: 0.0245 AC XY: 3321 AN XY: 135558

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.00894

Gnomad ASJ exome AF: 0.0228

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0396

Gnomad FIN exome AF: 0.0352

Gnomad NFE exome AF: 0.0257

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0261 AC: 37969 AN: 1456426 Hom.: 632 Cov.: 33 AF XY: 0.0265 AC XY: 19152 AN XY: 723252

Gnomad4 AFR exome AF: 0.00404

Gnomad4 AMR exome AF: 0.00903

Gnomad4 ASJ exome AF: 0.0222

Gnomad4 EAS exome AF: 0.000911

Gnomad4 SAS exome AF: 0.0398

Gnomad4 FIN exome AF: 0.0354

Gnomad4 NFE exome AF: 0.0271

Gnomad4 OTH exome AF: 0.0226

GnomAD4 genome AF: 0.0178 AC: 2710 AN: 152350 Hom.: 46 Cov.: 33 AF XY: 0.0185 AC XY: 1377 AN XY: 74504

Gnomad4 AFR AF: 0.00373

Gnomad4 AMR AF: 0.0144

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0300

Gnomad4 FIN AF: 0.0370

Gnomad4 NFE AF: 0.0244

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0220 Hom.: 18

Bravo AF: 0.0152

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.0238

EpiControl AF: 0.0249

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

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. -

May 16, 2012

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 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

Apr 15, 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

- -

Autosomal dominant nocturnal frontal lobe epilepsy 4 Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.76
DANN	Benign	0.56

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: rs56298562; hg19: chr8-27320636; COSMIC: COSV53559202; COSMIC: COSV53559202;