15-32111781-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_000746.6(CHRNA7):c.241-9G>A 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 0.000544 in 1,545,516 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: CHRNA7 NM_000746.6 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0006264
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.435

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 15-32111781-G-A is Benign according to our data. Variant chr15-32111781-G-A is described in ClinVar as [Benign]. Clinvar id is 735528.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 409 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA7	NM_000746.6	c.241-9G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000306901.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA7	ENST00000306901.9	c.241-9G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000746.6	P1

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 409 AN: 152196 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00861

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000638 AC: 159 AN: 249224 Hom.: 0 AF XY: 0.000513 AC XY: 69 AN XY: 134518

Gnomad AFR exome AF: 0.00845

Gnomad AMR exome AF: 0.000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000335

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000311 AC: 433 AN: 1393202 Hom.: 0 Cov.: 22 AF XY: 0.000291 AC XY: 203 AN XY: 696584

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.000474

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000475

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000952

Gnomad4 OTH exome AF: 0.000673

GnomAD4 genome AF: 0.00268 AC: 408 AN: 152314 Hom.: 4 Cov.: 33 AF XY: 0.00267 AC XY: 199 AN XY: 74490

Gnomad4 AFR AF: 0.00856

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000998 Hom.: 1

Bravo AF: 0.00321

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	14
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00063
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.010		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: rs148971791; hg19: chr15-32403982;