rs758217117

Variant names:

• chr8-27467228-CTTG-C
• rs758217117
• NM_000742.4:c.447_449delCAA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM4_Supporting PP3_Moderate BS2

The NM_000742.4(CHRNA2):​c.447_449delCAA​(p.Asn150del) variant causes a disruptive inframe deletion, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000993 in 1,611,620 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: CHRNA2 NM_000742.4 disruptive_inframe_deletion, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.99
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000742.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

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.447_449delCAA	p.Asn150del	disruptive_inframe_deletion splice_region	Exon 5 of 7	NP_000733.2
	CHRNA2	NM_001282455.2		c.402_404delCAA	p.Asn135del	disruptive_inframe_deletion splice_region	Exon 5 of 7	NP_001269384.1
	CHRNA2	NM_001347705.2		c.-26_-24delCAA		splice_region	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.447_449delCAA	p.Asn150del	disruptive_inframe_deletion splice_region	Exon 5 of 7	ENSP00000385026.1
	CHRNA2	ENST00000520600.1	TSL:1	n.287_289delCAA		splice_region non_coding_transcript_exon	Exon 1 of 2
	CHRNA2	ENST00000523695.5	TSL:1	n.447_449delCAA		splice_region non_coding_transcript_exon	Exon 5 of 7	ENSP00000430612.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251454 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459388 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 726228

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.000112 AC: 5 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109782

Other (OTH) AF: 0.00 AC: 0 AN: 60290

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74368

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0404278), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Uncertain:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.447_449del, results in the deletion of 1 amino acid(s) of the CHRNA2 protein (p.Asn150del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758217117, gnomAD 0.009%). 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: 204983). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

Inborn genetic diseases Uncertain:1

Apr 27, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.447_449delCAA variant (also known as p.N150DEL) is located in coding exon 4 of the CHRNA2 gene. This variant results from an in-frame CAA deletion of between nucleotide positions 447 and 449. The asparagine at codon 150 is deleted. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

not provided Uncertain:1

Jul 15, 2015

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.447_449delCAA variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It results in an in-frame deletion of a highly conserved amino acid residue, Asparagine 150. However, mutations in CHRNA2 have not been previously published in this region of the protein, and no in-frame deletions of CHRNA2 have been reported. Although c.447_449delCAA deletes the last three nucleotides of exon 5, multiple in silico algorithms predict that this variant will not impact splicing. Therefore, based on the currently available information, it is unclear whether c.447_449delCAA is a disease-causing mutation or a rare benign variant

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: 4
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs758217117; hg19: chr8-27324745;