chr15-32057761-T-C

Variant names:

• chr15-32057761-T-C
• rs4779971
• NM_000746.6:c.195+26724T>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.195+26724T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 152,072 control chromosomes in the GnomAD database, including 31,802 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 0.60 (31802 hom., cov: 32)
• Consequence: CHRNA7 NM_000746.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.978
• Publications: 1 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA7	NM_000746.6	c.195+26724T>C		intron_variant	Intron 2 of 9	ENST00000306901.9	NP_000737.1
CHRNA7	NM_001190455.3	c.282+26724T>C		intron_variant	Intron 2 of 9		NP_001177384.1
CHRNA7	NR_046324.1	n.307+26724T>C		intron_variant	Intron 2 of 7
CHRNA7	XM_011521178.4	c.195+26724T>C		intron_variant	Intron 2 of 8		XP_011519480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA7	ENST00000306901.9	c.195+26724T>C		intron_variant	Intron 2 of 9	1	NM_000746.6	ENSP00000303727.2

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91979 AN: 151954 Hom.: 31815 Cov.: 32

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.739

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.717

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.751

Gnomad FIN AF: 0.851

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.775

Gnomad OTH AF: 0.618

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

GnomAD4 genome AF: 0.605 AC: 91977 AN: 152072 Hom.: 31802 Cov.: 32 AF XY: 0.610 AC XY: 45344 AN XY: 74362

African (AFR) AF: 0.283 AC: 11753 AN: 41462

American (AMR) AF: 0.582 AC: 8889 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 2485 AN: 3466

East Asian (EAS) AF: 0.267 AC: 1379 AN: 5168

South Asian (SAS) AF: 0.750 AC: 3620 AN: 4828

European-Finnish (FIN) AF: 0.851 AC: 9011 AN: 10590

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.775 AC: 52671 AN: 67982

Other (OTH) AF: 0.615 AC: 1295 AN: 2104

Alfa AF: 0.671 Hom.: 4635

Bravo AF: 0.566

Asia WGS AF: 0.508 AC: 1768 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	14
DANN	Benign	0.84
PhyloP100		0.98
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: rs4779971; hg19: chr15-32349964;