15-32092916-T-C

Variant names:

• chr15-32092916-T-C
• rs6494212
• NM_000746.6:c.196-8387T>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.196-8387T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 152,010 control chromosomes in the GnomAD database, including 37,794 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 0.70 (37794 hom., cov: 31)
• Consequence: CHRNA7 NM_000746.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.111
• Publications: 11 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.891 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA7	NM_000746.6	MANE Select	c.196-8387T>C		intron	N/A	NP_000737.1
	CHRNA7	NM_001190455.3		c.283-8387T>C		intron	N/A	NP_001177384.1
	CHRNA7	NR_046324.1		n.308-8387T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA7	ENST00000306901.9	TSL:1 MANE Select	c.196-8387T>C		intron	N/A	ENSP00000303727.2
	CHRNA7	ENST00000635759.1	TSL:1	n.61-8387T>C		intron	N/A	ENSP00000489825.1
	CHRNA7	ENST00000637786.2	TSL:1	n.196-8387T>C		intron	N/A	ENSP00000490015.1

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106782 AN: 151892 Hom.: 37775 Cov.: 31

Gnomad AFR AF: 0.657

Gnomad AMI AF: 0.716

Gnomad AMR AF: 0.752

Gnomad ASJ AF: 0.739

Gnomad EAS AF: 0.913

Gnomad SAS AF: 0.804

Gnomad FIN AF: 0.754

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.688

Gnomad OTH AF: 0.689

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

GnomAD4 genome AF: 0.703 AC: 106839 AN: 152010 Hom.: 37794 Cov.: 31 AF XY: 0.709 AC XY: 52699 AN XY: 74304

African (AFR) AF: 0.657 AC: 27211 AN: 41436

American (AMR) AF: 0.752 AC: 11503 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 2567 AN: 3472

East Asian (EAS) AF: 0.913 AC: 4707 AN: 5156

South Asian (SAS) AF: 0.802 AC: 3864 AN: 4816

European-Finnish (FIN) AF: 0.754 AC: 7985 AN: 10584

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.688 AC: 46716 AN: 67934

Other (OTH) AF: 0.692 AC: 1465 AN: 2116

Alfa AF: 0.688 Hom.: 56247

Bravo AF: 0.700

Asia WGS AF: 0.857 AC: 2983 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	4.3
DANN	Benign	0.85
PhyloP100		-0.11
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: rs6494212; hg19: chr15-32385119; COSMIC: COSV60975533;