rs2337980

Variant names:

• chr15-32151995-C-T
• rs2337980
• NM_000746.6:c.351-1912C>T

Variant summary

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

The NM_000746.6(CHRNA7):​c.351-1912C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 152,056 control chromosomes in the GnomAD database, including 15,241 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 0.44 (15241 hom., cov: 32)
• Consequence: CHRNA7 NM_000746.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0490
• Publications: 31 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA7	NM_000746.6	c.351-1912C>T		intron_variant	Intron 4 of 9	ENST00000306901.9	NP_000737.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA7	ENST00000306901.9	c.351-1912C>T		intron_variant	Intron 4 of 9	1	NM_000746.6	ENSP00000303727.2

Frequencies

GnomAD3 genomes AF: 0.443 AC: 67348 AN: 151938 Hom.: 15219 Cov.: 32

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.446

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

GnomAD4 genome AF: 0.443 AC: 67401 AN: 152056 Hom.: 15241 Cov.: 32 AF XY: 0.436 AC XY: 32416 AN XY: 74306

African (AFR) AF: 0.488 AC: 20255 AN: 41480

American (AMR) AF: 0.400 AC: 6120 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1576 AN: 3472

East Asian (EAS) AF: 0.249 AC: 1284 AN: 5164

South Asian (SAS) AF: 0.268 AC: 1291 AN: 4818

European-Finnish (FIN) AF: 0.410 AC: 4331 AN: 10572

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.458 AC: 31105 AN: 67944

Other (OTH) AF: 0.446 AC: 942 AN: 2114

Alfa AF: 0.455 Hom.: 12588

Bravo AF: 0.446

Asia WGS AF: 0.274 AC: 952 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.4
DANN	Benign	0.60
PhyloP100		-0.049
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: rs2337980; hg19: chr15-32444196;