15-32030401-G-C

Variant names:

• chr15-32030401-G-C
• rs28531779
• ENST00000636603.1:c.-131-497G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000636603.1(CHRNA7):​c.-131-497G>C variant causes a 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: CHRNA7 ENST00000636603.1 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.149
• Publications: 10 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 -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
CHRNA7	NM_000746.6	c.-194G>C		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.-194G>C		upstream_gene_variant		1	NM_000746.6	ENSP00000303727.2

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

African (AFR) AF: 0.00905 AC: 41 AN: 4528

American (AMR) AF: 0.0491 AC: 212 AN: 4316

Ashkenazi Jewish (ASJ) AF: 0.0587 AC: 316 AN: 5386

East Asian (EAS) AF: 0.0804 AC: 1018 AN: 12662

South Asian (SAS) AF: 0.0434 AC: 93 AN: 2144

European-Finnish (FIN) AF: 0.0229 AC: 335 AN: 14612

Middle Eastern (MID) AF: 0.0897 AC: 77 AN: 858

European-Non Finnish (NFE) AF: 0.0399 AC: 5229 AN: 131042

Other (OTH) AF: 0.0483 AC: 524 AN: 10850

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

African (AFR) AF: 0.00971 AC: 373 AN: 38404

American (AMR) AF: 0.0467 AC: 681 AN: 14570

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 191 AN: 3318

East Asian (EAS) AF: 0.0673 AC: 309 AN: 4592

South Asian (SAS) AF: 0.0489 AC: 206 AN: 4214

European-Finnish (FIN) AF: 0.0183 AC: 172 AN: 9396

Middle Eastern (MID) AF: 0.102 AC: 29 AN: 284

European-Non Finnish (NFE) AF: 0.0402 AC: 2579 AN: 64172

Other (OTH) AF: 0.0416 AC: 81 AN: 1948

Alfa AF: 0.0122 Hom.: 7

Bravo AF: 0.0368

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 04, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.15
PromoterAI		0.053	Neutral

Splicing

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

Other links and lift over

dbSNP: rs28531779; hg19: chr15-32322604;