rs2133965

Positions:

• chr15-32092351-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000746.6(CHRNA7):​c.196-8952A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.825 in 152,232 control chromosomes in the GnomAD database, including 53,346 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 0.83 (53346 hom., cov: 33)
• Consequence: CHRNA7 NM_000746.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.198

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.924 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA7	NM_000746.6	c.196-8952A>G		intron_variant		ENST00000306901.9
CHRNA7	NM_001190455.3	c.283-8952A>G		intron_variant
CHRNA7	XM_011521178.4	c.196-8952A>G		intron_variant
CHRNA7	NR_046324.1	n.308-8952A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA7	ENST00000306901.9	c.196-8952A>G		intron_variant		1	NM_000746.6	P1

Frequencies

GnomAD3 genomes AF: 0.826 AC: 125583 AN: 152114 Hom.: 53347 Cov.: 33

Gnomad AFR AF: 0.607

Gnomad AMI AF: 0.940

Gnomad AMR AF: 0.822

Gnomad ASJ AF: 0.927

Gnomad EAS AF: 0.796

Gnomad SAS AF: 0.911

Gnomad FIN AF: 0.937

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.841

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

GnomAD4 genome AF: 0.825 AC: 125623 AN: 152232 Hom.: 53346 Cov.: 33 AF XY: 0.826 AC XY: 61498 AN XY: 74428

Gnomad4 AFR AF: 0.607

Gnomad4 AMR AF: 0.821

Gnomad4 ASJ AF: 0.927

Gnomad4 EAS AF: 0.796

Gnomad4 SAS AF: 0.911

Gnomad4 FIN AF: 0.937

Gnomad4 NFE AF: 0.931

Gnomad4 OTH AF: 0.841

Alfa AF: 0.905 Hom.: 19503

Bravo AF: 0.807

Asia WGS AF: 0.848 AC: 2949 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.78
DANN	Benign	0.81

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: rs2133965; hg19: chr15-32384554;