15-32030401-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The XM_047433397.1(LOC124903441):c.41-13C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0381 in 328,138 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (118 hom., cov: 19)
  • Exomes 𝑓: 0.042 (198 hom.)
• Consequence: LOC124903441 XM_047433397.1 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.149

Genes affected

LOC124903441 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 15-32030401-G-C is Benign according to our data. Variant chr15-32030401-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1208572.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC124903441	XM_047433397.1	c.41-13C>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA7	ENST00000635884.1	c.-132+427G>C		intron_variant		5
CHRNA7	ENST00000635978.1	c.-42-70902G>C		intron_variant		5
CHRNA7	ENST00000636603.1	c.-131-497G>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0328 AC: 4650 AN: 141658 Hom.: 118 Cov.: 19

Gnomad AFR AF: 0.00977

Gnomad AMI AF: 0.0344

Gnomad AMR AF: 0.0469

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.0668

Gnomad SAS AF: 0.0488

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0980

Gnomad NFE AF: 0.0402

Gnomad OTH AF: 0.0404

GnomAD4 exome AF: 0.0421 AC: 7845 AN: 186398 Hom.: 198 AF XY: 0.0427 AC XY: 4041 AN XY: 94630

Gnomad4 AFR exome AF: 0.00905

Gnomad4 AMR exome AF: 0.0491

Gnomad4 ASJ exome AF: 0.0587

Gnomad4 EAS exome AF: 0.0804

Gnomad4 SAS exome AF: 0.0434

Gnomad4 FIN exome AF: 0.0229

Gnomad4 NFE exome AF: 0.0399

Gnomad4 OTH exome AF: 0.0483

GnomAD4 genome AF: 0.0328 AC: 4650 AN: 141740 Hom.: 118 Cov.: 19 AF XY: 0.0321 AC XY: 2217 AN XY: 69020

Gnomad4 AFR AF: 0.00971

Gnomad4 AMR AF: 0.0467

Gnomad4 ASJ AF: 0.0576

Gnomad4 EAS AF: 0.0673

Gnomad4 SAS AF: 0.0489

Gnomad4 FIN AF: 0.0183

Gnomad4 NFE AF: 0.0402

Gnomad4 OTH AF: 0.0416

Alfa AF: 0.0122 Hom.: 7

Bravo AF: 0.0368

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 2020

This variant is associated with the following publications: (PMID: 14569275) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	6.8
Dann	Benign	0.64

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs28531779; hg19: chr15-32322604;