15-32030404-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000636603.1(CHRNA7):​c.-131-494G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 333,836 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (14 hom., cov: 19)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: CHRNA7 ENST00000636603.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 15-32030404-G-A is Benign according to our data. Variant chr15-32030404-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1198672.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00717 (1015/141500) while in subpopulation AFR AF = 0.0248 (942/37938). AF 95% confidence interval is 0.0235. There are 14 homozygotes in GnomAd4. There are 471 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1015 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA7	NM_000746.6	c.-191G>A		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>A		upstream_gene_variant		1	NM_000746.6	ENSP00000303727.2

Frequencies

GnomAD3 genomes AF: 0.00716 AC: 1012 AN: 141412 Hom.: 14 Cov.: 19

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00233

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000467

Gnomad OTH AF: 0.00468

GnomAD4 exome AF: 0.00112 AC: 216 AN: 192336 Hom.: 3 AF XY: 0.00103 AC XY: 101 AN XY: 97632

African (AFR) AF: 0.0229 AC: 106 AN: 4632

American (AMR) AF: 0.00297 AC: 13 AN: 4378

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 13004

South Asian (SAS) AF: 0.00266 AC: 6 AN: 2252

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

Middle Eastern (MID) AF: 0.00452 AC: 4 AN: 884

European-Non Finnish (NFE) AF: 0.000390 AC: 53 AN: 135758

Other (OTH) AF: 0.00305 AC: 34 AN: 11158

GnomAD4 genome AF: 0.00717 AC: 1015 AN: 141500 Hom.: 14 Cov.: 19 AF XY: 0.00684 AC XY: 471 AN XY: 68868

African (AFR) AF: 0.0248 AC: 942 AN: 37938

American (AMR) AF: 0.00164 AC: 24 AN: 14628

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4652

South Asian (SAS) AF: 0.00233 AC: 10 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: 0.000467 AC: 30 AN: 64232

Other (OTH) AF: 0.00464 AC: 9 AN: 1940

Alfa AF: 0.000484 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 05, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.96
PhyloP100		1.3
PromoterAI		-0.28	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;