NM_000746.6:c.196-6_196-5dupTT

Variant names:

• chr15-32101283-C-CTT
• rs34476605
• NM_000746.6:c.196-6_196-5dupTT

Variant summary

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

The NM_000746.6(CHRNA7):​c.196-6_196-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (8898 hom., cov: 0)
  • Exomes 𝑓: 0.26 (1708 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-CTT is Benign according to our data. Variant chr15-32101283-C-CTT is described in ClinVar as Benign. ClinVar VariationId is 1180278.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.576 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.196-6_196-5dupTT		splice_region intron	N/A	NP_000737.1	P36544-1
	CHRNA7	NM_001190455.3		c.283-6_283-5dupTT		splice_region intron	N/A	NP_001177384.1	P36544-2
	CHRNA7	NR_046324.1		n.308-6_308-5dupTT		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.196-6_196-5dupTT		splice_region intron	N/A	ENSP00000303727.2	P36544-1
	CHRNA7	ENST00000635759.1	TSL:1	n.61-6_61-5dupTT		splice_region intron	N/A	ENSP00000489825.1	A0A1B0GTT0
	CHRNA7	ENST00000637786.2	TSL:1	n.196-6_196-5dupTT		splice_region intron	N/A	ENSP00000490015.1	A0A1B0GU93

Frequencies

GnomAD3 genomes AF: 0.348 AC: 49098 AN: 141220 Hom.: 8904 Cov.: 0

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.594

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.327

Gnomad NFE AF: 0.374

Gnomad OTH AF: 0.357

GnomAD2 exomes AF: 0.196 AC: 28911 AN: 147816 AF XY: 0.193

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.185

Gnomad EAS exome AF: 0.264

Gnomad FIN exome AF: 0.201

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.202

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.256 AC: 326983 AN: 1277724 Hom.: 1708 Cov.: 26 AF XY: 0.254 AC XY: 161826 AN XY: 636316

African (AFR) AF: 0.171 AC: 4747 AN: 27768

American (AMR) AF: 0.203 AC: 5835 AN: 28686

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 4913 AN: 22170

East Asian (EAS) AF: 0.323 AC: 11331 AN: 35066

South Asian (SAS) AF: 0.218 AC: 15275 AN: 69940

European-Finnish (FIN) AF: 0.240 AC: 11069 AN: 46074

Middle Eastern (MID) AF: 0.222 AC: 1094 AN: 4938

European-Non Finnish (NFE) AF: 0.262 AC: 259476 AN: 990394

Other (OTH) AF: 0.251 AC: 13243 AN: 52688

GnomAD4 genome AF: 0.348 AC: 49088 AN: 141222 Hom.: 8898 Cov.: 0 AF XY: 0.348 AC XY: 23676 AN XY: 67992

African (AFR) AF: 0.256 AC: 9800 AN: 38336

American (AMR) AF: 0.363 AC: 5160 AN: 14226

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 1212 AN: 3394

East Asian (EAS) AF: 0.594 AC: 2874 AN: 4840

South Asian (SAS) AF: 0.379 AC: 1671 AN: 4406

European-Finnish (FIN) AF: 0.367 AC: 2699 AN: 7358

Middle Eastern (MID) AF: 0.339 AC: 95 AN: 280

European-Non Finnish (NFE) AF: 0.374 AC: 24521 AN: 65548

Other (OTH) AF: 0.360 AC: 698 AN: 1938

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		=28/72	disease causing

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34476605; hg19: chr15-32393486; COSMIC: COSV60975335;