chr15-32157673-CTG-C

Variant names:

• chr15-32157673-CTG-C
• rs67158670
• NM_000746.6:c.497_498delTG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000746.6(CHRNA7):​c.497_498delTG​(p.Leu166GlnfsTer41) variant causes a frameshift change involving the alteration of a conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 12)
  • Exomes 𝑓: 0.000033 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRNA7 NM_000746.6 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.58
• Publications: 13 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

ENSG00000301688 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA7	NM_000746.6	c.497_498delTG	p.Leu166GlnfsTer41	frameshift_variant	Exon 6 of 10	ENST00000306901.9	NP_000737.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA7	ENST00000306901.9	c.497_498delTG	p.Leu166GlnfsTer41	frameshift_variant	Exon 6 of 10	1	NM_000746.6	ENSP00000303727.2

Frequencies

GnomAD3 genomes AF: 0.0000326 AC: 3 AN: 92150 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000530

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000871

GnomAD2 exomes AF: 0.0000325 AC: 6 AN: 184842 AF XY: 0.0000199

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000760

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000124

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000255

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000333 AC: 36 AN: 1080918 Hom.: 2 AF XY: 0.0000257 AC XY: 14 AN XY: 545032

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

African (AFR) AF: 0.00 AC: 0 AN: 23652

American (AMR) AF: 0.0000516 AC: 2 AN: 38734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20752

East Asian (EAS) AF: 0.0000822 AC: 3 AN: 36506

South Asian (SAS) AF: 0.0000529 AC: 4 AN: 75666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45646

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4538

European-Non Finnish (NFE) AF: 0.0000317 AC: 25 AN: 789646

Other (OTH) AF: 0.0000437 AC: 2 AN: 45778

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000325 AC: 3 AN: 92234 Hom.: 0 Cov.: 12 AF XY: 0.0000224 AC XY: 1 AN XY: 44598

African (AFR) AF: 0.00 AC: 0 AN: 21218

American (AMR) AF: 0.00 AC: 0 AN: 9292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2356

East Asian (EAS) AF: 0.000531 AC: 2 AN: 3764

South Asian (SAS) AF: 0.00 AC: 0 AN: 3208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 208

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 43936

Other (OTH) AF: 0.000858 AC: 1 AN: 1166

Alfa AF: 0.0115 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=2/198	disease causing (fs/PTC)

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: rs67158670; hg19: chr15-32449874; COSMIC: COSV60967667; COSMIC: COSV60967667;