NM_000746.6:c.1269C>T

Variant names:

• chr15-32168218-C-T
• rs1042724
• NM_000746.6:c.1269C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_000746.6(CHRNA7):​c.1269C>T​(p.Gly423Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.38 (1257 hom., cov: 16)
  • Exomes 𝑓: 0.40 (12214 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRNA7 NM_000746.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 9 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA7	NM_000746.6	c.1269C>T	p.Gly423Gly	synonymous_variant	Exon 10 of 10	ENST00000306901.9	NP_000737.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA7	ENST00000306901.9	c.1269C>T	p.Gly423Gly	synonymous_variant	Exon 10 of 10	1	NM_000746.6	ENSP00000303727.2

Frequencies

GnomAD3 genomes AF: 0.378 AC: 43234 AN: 114438 Hom.: 1252 Cov.: 16

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.376

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.377

GnomAD2 exomes AF: 0.383 AC: 40664 AN: 106130 AF XY: 0.383

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.377

Gnomad ASJ exome AF: 0.421

Gnomad EAS exome AF: 0.300

Gnomad FIN exome AF: 0.421

Gnomad NFE exome AF: 0.409

Gnomad OTH exome AF: 0.387

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.398 AC: 522327 AN: 1312490 Hom.: 12214 Cov.: 40 AF XY: 0.397 AC XY: 257444 AN XY: 648578

African (AFR) AF: 0.356 AC: 10714 AN: 30136

American (AMR) AF: 0.379 AC: 13691 AN: 36118

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 9856 AN: 23100

East Asian (EAS) AF: 0.324 AC: 11743 AN: 36240

South Asian (SAS) AF: 0.349 AC: 26238 AN: 75194

European-Finnish (FIN) AF: 0.413 AC: 18984 AN: 45942

Middle Eastern (MID) AF: 0.392 AC: 1493 AN: 3810

European-Non Finnish (NFE) AF: 0.405 AC: 408366 AN: 1007726

Other (OTH) AF: 0.392 AC: 21242 AN: 54224

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.378 AC: 43274 AN: 114544 Hom.: 1257 Cov.: 16 AF XY: 0.377 AC XY: 20781 AN XY: 55128

African (AFR) AF: 0.343 AC: 10175 AN: 29642

American (AMR) AF: 0.369 AC: 4233 AN: 11464

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1150 AN: 2838

East Asian (EAS) AF: 0.308 AC: 1119 AN: 3634

South Asian (SAS) AF: 0.324 AC: 1025 AN: 3162

European-Finnish (FIN) AF: 0.407 AC: 3022 AN: 7424

Middle Eastern (MID) AF: 0.380 AC: 73 AN: 192

European-Non Finnish (NFE) AF: 0.400 AC: 21594 AN: 53972

Other (OTH) AF: 0.375 AC: 553 AN: 1474

Alfa AF: 0.303 Hom.: 253

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.94
DANN	Benign	0.59
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs1042724; hg19: chr15-32460419; COSMIC: COSV60967340; COSMIC: COSV60967340;