15-32101283-C-CT

Variant names:

• chr15-32101283-C-CT
• rs34476605
• NM_000746.6:c.196-5dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000746.6(CHRNA7):​c.196-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (9812 hom., cov: 0)
  • Exomes 𝑓: 0.35 (2312 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRNA7 NM_000746.6 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.508
• Publications: 1 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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 15-32101283-C-CT is Benign according to our data. Variant chr15-32101283-C-CT is described in ClinVar as Benign. ClinVar VariationId is 1260396.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000746.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA7	NM_000746.6	MANE Select	c.196-5dupT		splice_region intron	N/A	NP_000737.1	P36544-1
	CHRNA7	NM_001190455.3		c.283-5dupT		splice_region intron	N/A	NP_001177384.1	P36544-2
	CHRNA7	NR_046324.1		n.308-5dupT		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA7	ENST00000306901.9	TSL:1 MANE Select	c.196-5dupT		splice_region intron	N/A	ENSP00000303727.2	P36544-1
	CHRNA7	ENST00000635759.1	TSL:1	n.61-5dupT		splice_region intron	N/A	ENSP00000489825.1	A0A1B0GTT0
	CHRNA7	ENST00000637786.2	TSL:1	n.196-5dupT		splice_region intron	N/A	ENSP00000490015.1	A0A1B0GU93

Frequencies

GnomAD3 genomes AF: 0.367 AC: 51788 AN: 141186 Hom.: 9805 Cov.: 0

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.446

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.0954

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.397

GnomAD2 exomes AF: 0.347 AC: 51230 AN: 147816 AF XY: 0.348

Gnomad AFR exome AF: 0.313

Gnomad AMR exome AF: 0.295

Gnomad ASJ exome AF: 0.354

Gnomad EAS exome AF: 0.264

Gnomad FIN exome AF: 0.374

Gnomad NFE exome AF: 0.378

Gnomad OTH exome AF: 0.347

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.349 AC: 444503 AN: 1273894 Hom.: 2312 Cov.: 26 AF XY: 0.347 AC XY: 220125 AN XY: 634480

African (AFR) AF: 0.286 AC: 7968 AN: 27870

American (AMR) AF: 0.271 AC: 7643 AN: 28208

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 7697 AN: 22124

East Asian (EAS) AF: 0.243 AC: 8461 AN: 34772

South Asian (SAS) AF: 0.264 AC: 18471 AN: 69980

European-Finnish (FIN) AF: 0.331 AC: 15185 AN: 45812

Middle Eastern (MID) AF: 0.383 AC: 1903 AN: 4972

European-Non Finnish (NFE) AF: 0.364 AC: 359212 AN: 987368

Other (OTH) AF: 0.340 AC: 17963 AN: 52788

GnomAD4 genome AF: 0.367 AC: 51794 AN: 141188 Hom.: 9812 Cov.: 0 AF XY: 0.359 AC XY: 24391 AN XY: 67986

African (AFR) AF: 0.325 AC: 12450 AN: 38328

American (AMR) AF: 0.338 AC: 4806 AN: 14232

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 1471 AN: 3392

East Asian (EAS) AF: 0.0958 AC: 465 AN: 4854

South Asian (SAS) AF: 0.250 AC: 1104 AN: 4422

European-Finnish (FIN) AF: 0.352 AC: 2590 AN: 7360

Middle Eastern (MID) AF: 0.500 AC: 139 AN: 278

European-Non Finnish (NFE) AF: 0.422 AC: 27602 AN: 65482

Other (OTH) AF: 0.395 AC: 767 AN: 1944

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.51
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs34476605; hg19: chr15-32393486;