15-32101283-CTTTTTTT-CTTTT

Variant names:

• chr15-32101283-CTTT-C
• rs34476605
• NM_000746.6:c.196-7_196-5delTTT

Variant summary

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

The NM_000746.6(CHRNA7):​c.196-7_196-5delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,309,178 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRNA7 NM_000746.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.160
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.196-7_196-5delTTT		splice_region intron	N/A	NP_000737.1	P36544-1
	CHRNA7	NM_001190455.3		c.283-7_283-5delTTT		splice_region intron	N/A	NP_001177384.1	P36544-2
	CHRNA7	NR_046324.1		n.308-7_308-5delTTT		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.196-7_196-5delTTT		splice_region intron	N/A	ENSP00000303727.2	P36544-1
	CHRNA7	ENST00000635759.1	TSL:1	n.61-7_61-5delTTT		splice_region intron	N/A	ENSP00000489825.1	A0A1B0GTT0
	CHRNA7	ENST00000637786.2	TSL:1	n.196-7_196-5delTTT		splice_region intron	N/A	ENSP00000490015.1	A0A1B0GU93

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 141326 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000192 AC: 251 AN: 1309178 Hom.: 0 AF XY: 0.000179 AC XY: 117 AN XY: 652572

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

African (AFR) AF: 0.000527 AC: 15 AN: 28488

American (AMR) AF: 0.000888 AC: 26 AN: 29284

Ashkenazi Jewish (ASJ) AF: 0.000220 AC: 5 AN: 22762

East Asian (EAS) AF: 0.000355 AC: 13 AN: 36592

South Asian (SAS) AF: 0.000609 AC: 44 AN: 72264

European-Finnish (FIN) AF: 0.0000633 AC: 3 AN: 47424

Middle Eastern (MID) AF: 0.000198 AC: 1 AN: 5046

European-Non Finnish (NFE) AF: 0.000127 AC: 129 AN: 1013106

Other (OTH) AF: 0.000277 AC: 15 AN: 54212

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 141326 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 68022

African (AFR) AF: 0.00 AC: 0 AN: 38300

American (AMR) AF: 0.00 AC: 0 AN: 14222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3396

East Asian (EAS) AF: 0.00 AC: 0 AN: 4874

South Asian (SAS) AF: 0.00 AC: 0 AN: 4452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65582

Other (OTH) AF: 0.00 AC: 0 AN: 1936

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
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;