15-32101299-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000746.6(CHRNA7):c.196-4G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (0 hom., cov: 18)
  • Exomes 𝑓: 0.0035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRNA7 NM_000746.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002205
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.331

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-32101299-G-T is Benign according to our data. Variant chr15-32101299-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 776869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome at 575 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA7	NM_000746.6	c.196-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000306901.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA7	ENST00000306901.9	c.196-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000746.6	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 397 AN: 67556 Hom.: 0 Cov.: 18 FAILED QC

Gnomad AFR AF: 0.00407

Gnomad AMI AF: 0.0155

Gnomad AMR AF: 0.00534

Gnomad ASJ AF: 0.00436

Gnomad EAS AF: 0.00746

Gnomad SAS AF: 0.00614

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0133

Gnomad NFE AF: 0.00601

Gnomad OTH AF: 0.00776

GnomAD3 exomes AF: 0.00769 AC: 575 AN: 74748 Hom.: 0 AF XY: 0.00699 AC XY: 287 AN XY: 41048

Gnomad AFR exome AF: 0.00526

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.00602

Gnomad EAS exome AF: 0.0220

Gnomad SAS exome AF: 0.00564

Gnomad FIN exome AF: 0.0137

Gnomad NFE exome AF: 0.00556

Gnomad OTH exome AF: 0.00909

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00354 AC: 3123 AN: 882590 Hom.: 0 Cov.: 34 AF XY: 0.00353 AC XY: 1545 AN XY: 437474

Gnomad4 AFR exome AF: 0.00337

Gnomad4 AMR exome AF: 0.0155

Gnomad4 ASJ exome AF: 0.00498

Gnomad4 EAS exome AF: 0.00649

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.0111

Gnomad4 NFE exome AF: 0.00238

Gnomad4 OTH exome AF: 0.00341

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00589 AC: 398 AN: 67586 Hom.: 0 Cov.: 18 AF XY: 0.00670 AC XY: 218 AN XY: 32538

Gnomad4 AFR AF: 0.00412

Gnomad4 AMR AF: 0.00533

Gnomad4 ASJ AF: 0.00436

Gnomad4 EAS AF: 0.00751

Gnomad4 SAS AF: 0.00618

Gnomad4 FIN AF: 0.0129

Gnomad4 NFE AF: 0.00601

Gnomad4 OTH AF: 0.00776

Alfa AF: 0.00120 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.2
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0
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: rs200648754; hg19: chr15-32393502; COSMIC: COSV60972272;