NM_000746.6:c.241-4268T>C

Variant names:

• chr15-32107522-T-C
• rs1500948
• NM_000746.6:c.241-4268T>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.241-4268T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 151,522 control chromosomes in the GnomAD database, including 6,994 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 0.30 (6994 hom., cov: 32)
• Consequence: CHRNA7 NM_000746.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0800
• Publications: 2 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=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.326 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.241-4268T>C		intron	N/A	NP_000737.1
	CHRNA7	NM_001190455.3		c.328-4268T>C		intron	N/A	NP_001177384.1
	CHRNA7	NR_046324.1		n.352+6175T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA7	ENST00000306901.9	TSL:1 MANE Select	c.241-4268T>C		intron	N/A	ENSP00000303727.2
	CHRNA7	ENST00000635759.1	TSL:1	n.106-4305T>C		intron	N/A	ENSP00000489825.1
	CHRNA7	ENST00000637786.2	TSL:1	n.241-4278T>C		intron	N/A	ENSP00000490015.1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44737 AN: 151422 Hom.: 6988 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.0657

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.285

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

GnomAD4 genome AF: 0.295 AC: 44770 AN: 151522 Hom.: 6994 Cov.: 32 AF XY: 0.291 AC XY: 21542 AN XY: 74052

African (AFR) AF: 0.288 AC: 11915 AN: 41354

American (AMR) AF: 0.224 AC: 3409 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 1049 AN: 3468

East Asian (EAS) AF: 0.0658 AC: 341 AN: 5182

South Asian (SAS) AF: 0.153 AC: 736 AN: 4812

European-Finnish (FIN) AF: 0.385 AC: 3973 AN: 10318

Middle Eastern (MID) AF: 0.253 AC: 74 AN: 292

European-Non Finnish (NFE) AF: 0.329 AC: 22347 AN: 67862

Other (OTH) AF: 0.283 AC: 594 AN: 2100

Alfa AF: 0.314 Hom.: 5758

Bravo AF: 0.285

Asia WGS AF: 0.108 AC: 377 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.0
DANN	Benign	0.61
PhyloP100		-0.080
Mutation Taster		=99/1	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: rs1500948; hg19: chr15-32399723;