rs12915265

Variant names:

• chr15-32116865-T-C
• rs12915265
• NM_000746.6:c.350+4966T>C

Variant summary

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

The NM_000746.6(CHRNA7):​c.350+4966T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 152,282 control chromosomes in the GnomAD database, including 2,389 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 0.16 (2389 hom., cov: 33)
• Consequence: CHRNA7 NM_000746.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.72
• Publications: 12 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000746.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA7	NM_000746.6	MANE Select	c.350+4966T>C		intron	N/A	NP_000737.1	P36544-1
	CHRNA7	NM_001190455.3		c.437+4966T>C		intron	N/A	NP_001177384.1	P36544-2
	CHRNA7	NR_046324.1		n.352+15518T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA7	ENST00000306901.9	TSL:1 MANE Select	c.350+4966T>C		intron	N/A	ENSP00000303727.2	P36544-1
	CHRNA7	ENST00000454250.7	TSL:2	c.437+4966T>C		intron	N/A	ENSP00000407546.3	P36544-2
	CHRNA7	ENST00000675428.1		c.437+4966T>C		intron	N/A	ENSP00000502560.1	P36544-2

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24774 AN: 152164 Hom.: 2388 Cov.: 33

Gnomad AFR AF: 0.0705

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.0402

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.186

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

GnomAD4 genome AF: 0.163 AC: 24772 AN: 152282 Hom.: 2389 Cov.: 33 AF XY: 0.160 AC XY: 11928 AN XY: 74460

African (AFR) AF: 0.0705 AC: 2928 AN: 41550

American (AMR) AF: 0.152 AC: 2331 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 763 AN: 3470

East Asian (EAS) AF: 0.0403 AC: 209 AN: 5186

South Asian (SAS) AF: 0.131 AC: 633 AN: 4818

European-Finnish (FIN) AF: 0.171 AC: 1813 AN: 10616

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15350 AN: 68014

Other (OTH) AF: 0.183 AC: 388 AN: 2116

Alfa AF: 0.202 Hom.: 1858

Bravo AF: 0.159

Asia WGS AF: 0.0800 AC: 276 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.73
PhyloP100		-1.7
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: rs12915265; hg19: chr15-32409066;