15-32101283-CTTTTTTT-CTTTTTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000746.6(CHRNA7):​c.196-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0322 in 1,413,606 control chromosomes in the GnomAD database, including 7 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (7 hom., cov: 0)
  • Exomes 𝑓: 0.035 (0 hom.)
• 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-CT-C is Benign according to our data. Variant chr15-32101283-CT-C is described in ClinVar as Benign. ClinVar VariationId is 1243266.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0053 (749/141272) while in subpopulation AFR AF = 0.0163 (626/38348). AF 95% confidence interval is 0.0153. There are 7 homozygotes in GnomAd4. There are 362 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 749 AD,Unknown gene.

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.196-5delT		splice_region intron	N/A	NP_000737.1	P36544-1
	CHRNA7	NM_001190455.3		c.283-5delT		splice_region intron	N/A	NP_001177384.1	P36544-2
	CHRNA7	NR_046324.1		n.308-5delT		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.196-5delT		splice_region intron	N/A	ENSP00000303727.2	P36544-1
	CHRNA7	ENST00000635759.1	TSL:1	n.61-5delT		splice_region intron	N/A	ENSP00000489825.1	A0A1B0GTT0
	CHRNA7	ENST00000637786.2	TSL:1	n.196-5delT		splice_region intron	N/A	ENSP00000490015.1	A0A1B0GU93

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 748 AN: 141270 Hom.: 7 Cov.: 0

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00211

Gnomad ASJ AF: 0.000589

Gnomad EAS AF: 0.000821

Gnomad SAS AF: 0.000449

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000686

Gnomad OTH AF: 0.00568

GnomAD2 exomes AF: 0.0653 AC: 9656 AN: 147816 AF XY: 0.0647

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.0657

Gnomad EAS exome AF: 0.0831

Gnomad FIN exome AF: 0.0416

Gnomad NFE exome AF: 0.0455

Gnomad OTH exome AF: 0.0712

GnomAD4 exome AF: 0.0352 AC: 44802 AN: 1272334 Hom.: 0 Cov.: 26 AF XY: 0.0361 AC XY: 22845 AN XY: 633634

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0830 AC: 2260 AN: 27234

American (AMR) AF: 0.0796 AC: 2236 AN: 28086

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 976 AN: 21968

East Asian (EAS) AF: 0.0499 AC: 1767 AN: 35398

South Asian (SAS) AF: 0.0742 AC: 5117 AN: 68970

European-Finnish (FIN) AF: 0.0380 AC: 1741 AN: 45844

Middle Eastern (MID) AF: 0.0311 AC: 153 AN: 4914

European-Non Finnish (NFE) AF: 0.0288 AC: 28484 AN: 987376

Other (OTH) AF: 0.0394 AC: 2068 AN: 52544

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00530 AC: 749 AN: 141272 Hom.: 7 Cov.: 0 AF XY: 0.00532 AC XY: 362 AN XY: 68014

African (AFR) AF: 0.0163 AC: 626 AN: 38348

American (AMR) AF: 0.00211 AC: 30 AN: 14238

Ashkenazi Jewish (ASJ) AF: 0.000589 AC: 2 AN: 3396

East Asian (EAS) AF: 0.000824 AC: 4 AN: 4854

South Asian (SAS) AF: 0.000452 AC: 2 AN: 4422

European-Finnish (FIN) AF: 0.00395 AC: 29 AN: 7348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000687 AC: 45 AN: 65544

Other (OTH) AF: 0.00565 AC: 11 AN: 1946

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		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs34476605; hg19: chr15-32393486;