15-32030404-G-T

Variant names:

• chr15-32030404-G-T
• rs553179500
• ENST00000636603.1:c.-131-494G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000636603.1(CHRNA7):​c.-131-494G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 333,844 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: 𝑓 0.000014 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CHRNA7 ENST00000636603.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA7	NM_000746.6	c.-191G>T		upstream_gene_variant		ENST00000306901.9	NP_000737.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA7	ENST00000306901.9	c.-191G>T		upstream_gene_variant		1	NM_000746.6	ENSP00000303727.2

Frequencies

GnomAD3 genomes AF: 0.0000141 AC: 2 AN: 141418 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000214

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000156

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000104 AC: 2 AN: 192338 Hom.: 0 AF XY: 0.0000102 AC XY: 1 AN XY: 97634

African (AFR) AF: 0.00 AC: 0 AN: 4632

American (AMR) AF: 0.00 AC: 0 AN: 4378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5498

East Asian (EAS) AF: 0.0000769 AC: 1 AN: 13004

South Asian (SAS) AF: 0.00 AC: 0 AN: 2252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 884

European-Non Finnish (NFE) AF: 0.00000737 AC: 1 AN: 135758

Other (OTH) AF: 0.00 AC: 0 AN: 11160

GnomAD4 genome AF: 0.0000141 AC: 2 AN: 141506 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 68870

African (AFR) AF: 0.00 AC: 0 AN: 37944

American (AMR) AF: 0.00 AC: 0 AN: 14628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3336

East Asian (EAS) AF: 0.000215 AC: 1 AN: 4652

South Asian (SAS) AF: 0.00 AC: 0 AN: 4288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.0000156 AC: 1 AN: 64232

Other (OTH) AF: 0.00 AC: 0 AN: 1940

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.87
PhyloP100		1.3
PromoterAI		-0.36	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs553179500; hg19: chr15-32322607;