rs8024987

Variant names:

• chr15-32044027-C-G
• rs8024987
• NM_000746.6:c.195+12990C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000746.6(CHRNA7):​c.195+12990C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 152,168 control chromosomes in the GnomAD database, including 4,745 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (4745 hom., cov: 33)
• Consequence: CHRNA7 NM_000746.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.815
• Publications: 14 publications found

Genes affected

CHRNA7 (HGNC:1960): (cholinergic receptor nicotinic alpha 7 subunit) The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The nAChRs are thought to be hetero-pentamers composed of homologous subunits. The proposed structure for each subunit 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. The protein encoded by this gene forms a homo-oligomeric channel, displays marked permeability to calcium ions and is a major component of brain nicotinic receptors that are blocked by, and highly sensitive to, alpha-bungarotoxin. Once this receptor binds acetylcholine, it undergoes an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. This gene is located in a region identified as a major susceptibility locus for juvenile myoclonic epilepsy and a chromosomal location involved in the genetic transmission of schizophrenia. An evolutionarily recent partial duplication event in this region results in a hybrid containing sequence from this gene and a novel FAM7A gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

CHRNA7 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• epilepsy

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA7	NM_000746.6	c.195+12990C>G		intron_variant	Intron 2 of 9	ENST00000306901.9	NP_000737.1
CHRNA7	NM_001190455.3	c.282+12990C>G		intron_variant	Intron 2 of 9		NP_001177384.1
CHRNA7	NR_046324.1	n.307+12990C>G		intron_variant	Intron 2 of 7
CHRNA7	XM_011521178.4	c.195+12990C>G		intron_variant	Intron 2 of 8		XP_011519480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA7	ENST00000306901.9	c.195+12990C>G		intron_variant	Intron 2 of 9	1	NM_000746.6	ENSP00000303727.2

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32845 AN: 152050 Hom.: 4745 Cov.: 33

Gnomad AFR AF: 0.0492

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.203

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.216 AC: 32827 AN: 152168 Hom.: 4745 Cov.: 33 AF XY: 0.226 AC XY: 16794 AN XY: 74376

African (AFR) AF: 0.0491 AC: 2040 AN: 41546

American (AMR) AF: 0.178 AC: 2725 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 889 AN: 3470

East Asian (EAS) AF: 0.102 AC: 526 AN: 5178

South Asian (SAS) AF: 0.401 AC: 1937 AN: 4826

European-Finnish (FIN) AF: 0.427 AC: 4517 AN: 10570

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19428 AN: 67966

Other (OTH) AF: 0.200 AC: 423 AN: 2116

Alfa AF: 0.260 Hom.: 748

Bravo AF: 0.185

Asia WGS AF: 0.253 AC: 878 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.43
DANN	Benign	0.36
PhyloP100		-0.81
Mutation Taster		=100/0	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: rs8024987; hg19: chr15-32336230;