NM_000746.6:c.-46G>A

Variant names:

• chr15-32030549-G-A
• rs145180415
• NM_000746.6:c.-46G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000746.6(CHRNA7):​c.-46G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000465 in 1,290,112 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000047 (0 hom.)
• Consequence: CHRNA7 NM_000746.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0270
• Publications: 0 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

LOC124903441 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS2: High AC in GnomAdExome4 at 6 AD,Unknown gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA7	NM_000746.6	MANE Select	c.-46G>A		5_prime_UTR	Exon 1 of 10	NP_000737.1	P36544-1
	CHRNA7	NM_001190455.3		c.-46G>A		5_prime_UTR	Exon 1 of 10	NP_001177384.1	P36544-2
	CHRNA7	NR_046324.1		n.67G>A		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA7	ENST00000306901.9	TSL:1 MANE Select	c.-46G>A		5_prime_UTR	Exon 1 of 10	ENSP00000303727.2	P36544-1
	CHRNA7	ENST00000454250.7	TSL:2	c.-46G>A		5_prime_UTR	Exon 1 of 10	ENSP00000407546.3	P36544-2
	CHRNA7	ENST00000675428.1		c.-46G>A		5_prime_UTR	Exon 1 of 10	ENSP00000502560.1	P36544-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000465 AC: 6 AN: 1290112 Hom.: 0 Cov.: 31 AF XY: 0.00000632 AC XY: 4 AN XY: 632904

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26058

American (AMR) AF: 0.00 AC: 0 AN: 22636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21322

East Asian (EAS) AF: 0.00 AC: 0 AN: 27994

South Asian (SAS) AF: 0.00 AC: 0 AN: 66748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32816

Middle Eastern (MID) AF: 0.000262 AC: 1 AN: 3814

European-Non Finnish (NFE) AF: 0.00000386 AC: 4 AN: 1035402

Other (OTH) AF: 0.0000188 AC: 1 AN: 53322

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00206180), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.2
DANN	Benign	0.88
PhyloP100		-0.027
PromoterAI		0.013	Neutral

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: rs145180415; hg19: chr15-32322752;