15-32125837-A-G

Variant names:

• chr15-32125837-A-G
• rs904951
• NM_000746.6:c.350+13938A>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.350+13938A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 151,972 control chromosomes in the GnomAD database, including 25,534 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 0.57 (25534 hom., cov: 31)
• Consequence: CHRNA7 NM_000746.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.743
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.697 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.350+13938A>G		intron	N/A	NP_000737.1
	CHRNA7	NM_001190455.3		c.437+13938A>G		intron	N/A	NP_001177384.1
	CHRNA7	NR_046324.1		n.352+24490A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA7	ENST00000306901.9	TSL:1 MANE Select	c.350+13938A>G		intron	N/A	ENSP00000303727.2
	CHRNA7	ENST00000454250.7	TSL:2	c.437+13938A>G		intron	N/A	ENSP00000407546.3
	CHRNA7	ENST00000675428.1		c.437+13938A>G		intron	N/A	ENSP00000502560.1

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86834 AN: 151852 Hom.: 25486 Cov.: 31

Gnomad AFR AF: 0.703

Gnomad AMI AF: 0.450

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.701

Gnomad SAS AF: 0.692

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.570

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

GnomAD4 genome AF: 0.572 AC: 86933 AN: 151972 Hom.: 25534 Cov.: 31 AF XY: 0.574 AC XY: 42651 AN XY: 74288

African (AFR) AF: 0.704 AC: 29155 AN: 41440

American (AMR) AF: 0.581 AC: 8882 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 1913 AN: 3466

East Asian (EAS) AF: 0.701 AC: 3604 AN: 5144

South Asian (SAS) AF: 0.691 AC: 3323 AN: 4806

European-Finnish (FIN) AF: 0.443 AC: 4678 AN: 10562

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.494 AC: 33589 AN: 67954

Other (OTH) AF: 0.569 AC: 1200 AN: 2110

Alfa AF: 0.528 Hom.: 52032

Bravo AF: 0.585

Asia WGS AF: 0.728 AC: 2530 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.67
PhyloP100		-0.74
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: rs904951; hg19: chr15-32418038;