15-32030726-G-A

Position:

• chr15-32030726-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000746.6(CHRNA7):​c.55+77G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0715 in 1,533,474 control chromosomes in the GnomAD database, including 5,030 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (408 hom., cov: 32)
  • Exomes 𝑓: 0.073 (4622 hom.)
• Consequence: CHRNA7 NM_000746.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.04

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 15-32030726-G-A is Benign according to our data. Variant chr15-32030726-G-A is described in ClinVar as [Benign]. Clinvar id is 1288527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA7	NM_000746.6	c.55+77G>A		intron_variant		ENST00000306901.9	NP_000737.1
CHRNA7	NM_001190455.3	c.132G>A	p.Ala44=	synonymous_variant	1/10		NP_001177384.1
CHRNA7	XM_011521178.4	c.55+77G>A		intron_variant			XP_011519480.1
CHRNA7	NR_046324.1	n.167+77G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA7	ENST00000306901.9	c.55+77G>A		intron_variant		1	NM_000746.6	ENSP00000303727	P1

Frequencies

GnomAD3 genomes AF: 0.0607 AC: 9224 AN: 151872 Hom.: 410 Cov.: 32

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0799

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0734

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.0639

Gnomad OTH AF: 0.0789

GnomAD3 exomes AF: 0.0968 AC: 12298 AN: 127086 Hom.: 739 AF XY: 0.0995 AC XY: 6980 AN XY: 70154

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.0892

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.148

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.0798

Gnomad NFE exome AF: 0.0707

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0727 AC: 100456 AN: 1381492 Hom.: 4622 Cov.: 32 AF XY: 0.0750 AC XY: 51099 AN XY: 681666

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.0869

Gnomad4 ASJ exome AF: 0.157

Gnomad4 EAS exome AF: 0.210

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.0747

Gnomad4 NFE exome AF: 0.0615

Gnomad4 OTH exome AF: 0.0861

GnomAD4 genome AF: 0.0607 AC: 9222 AN: 151982 Hom.: 408 Cov.: 32 AF XY: 0.0630 AC XY: 4677 AN XY: 74270

Gnomad4 AFR AF: 0.0145

Gnomad4 AMR AF: 0.0801

Gnomad4 ASJ AF: 0.156

Gnomad4 EAS AF: 0.160

Gnomad4 SAS AF: 0.139

Gnomad4 FIN AF: 0.0734

Gnomad4 NFE AF: 0.0638

Gnomad4 OTH AF: 0.0771

Alfa AF: 0.0545 Hom.: 87

Bravo AF: 0.0593

Asia WGS AF: 0.145 AC: 503 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	10
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2292571; hg19: chr15-32322929; COSMIC: COSV60970311; COSMIC: COSV60970311;