15-32025256-A-G

Variant names:

• chr15-32025256-A-G
• rs965435
• ENST00000636603.1:c.-131-5642A>G

Variant summary

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

The ENST00000636603.1(CHRNA7):​c.-131-5642A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.579 in 151,936 control chromosomes in the GnomAD database, including 28,876 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 0.58 (28876 hom., cov: 32)
• Consequence: CHRNA7 ENST00000636603.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.42
• Publications: 3 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=-1.03).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA7	ENST00000636603.1	c.-131-5642A>G		intron_variant	Intron 1 of 9	5		ENSP00000490513.1
CHRNA7	ENST00000637183.1	c.-43+47062A>G		intron_variant	Intron 1 of 8	5		ENSP00000490365.1
CHRNA7	ENST00000638106.1	c.-378-5642A>G		intron_variant	Intron 1 of 8	5		ENSP00000490413.1
CHRNA7	ENST00000635978.1	c.-42-76047A>G		intron_variant	Intron 1 of 6	5		ENSP00000490778.1

Frequencies

GnomAD3 genomes AF: 0.580 AC: 87984 AN: 151818 Hom.: 28884 Cov.: 32

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.660

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.693

Gnomad FIN AF: 0.834

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.579

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

GnomAD4 genome AF: 0.579 AC: 87978 AN: 151936 Hom.: 28876 Cov.: 32 AF XY: 0.583 AC XY: 43307 AN XY: 74268

African (AFR) AF: 0.300 AC: 12432 AN: 41448

American (AMR) AF: 0.540 AC: 8238 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.660 AC: 2288 AN: 3466

East Asian (EAS) AF: 0.191 AC: 990 AN: 5176

South Asian (SAS) AF: 0.692 AC: 3323 AN: 4800

European-Finnish (FIN) AF: 0.834 AC: 8797 AN: 10546

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.734 AC: 49883 AN: 67928

Other (OTH) AF: 0.575 AC: 1212 AN: 2108

Alfa AF: 0.670 Hom.: 124552

Bravo AF: 0.539

Asia WGS AF: 0.467 AC: 1618 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.026
DANN	Benign	0.52
PhyloP100		-2.4

Splicing

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

Other links and lift over

dbSNP: rs965435; hg19: chr15-32317459;