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GeneBe

15-32030620-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000746.6(CHRNA7):c.26G>T(p.Trp9Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,415,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CHRNA7
NM_000746.6 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.528
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19538859).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CHRNA7NM_000746.6 linkuse as main transcriptc.26G>T p.Trp9Leu missense_variant 1/10 ENST00000306901.9
LOC124903441XM_047433397.1 linkuse as main transcript upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CHRNA7ENST00000306901.9 linkuse as main transcriptc.26G>T p.Trp9Leu missense_variant 1/101 NM_000746.6 P1P36544-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000141
AC:
2
AN:
1415356
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
702246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000485
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 12, 2022The c.26G>T (p.W9L) alteration is located in exon 1 (coding exon 1) of the CHRNA7 gene. This alteration results from a G to T substitution at nucleotide position 26, causing the tryptophan (W) at amino acid position 9 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.018
T
BayesDel_noAF
Benign
-0.26
Cadd
Benign
22
Dann
Benign
0.91
DEOGEN2
Benign
0.34
T;.;.
Eigen
Benign
-0.75
Eigen_PC
Benign
-0.74
FATHMM_MKL
Benign
0.31
N
LIST_S2
Benign
0.70
T;T;T
M_CAP
Pathogenic
0.51
D
MetaRNN
Benign
0.20
T;T;T
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
0.13
N;N;.
MutationTaster
Benign
1.0
D;N;N
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-2.1
N;N;.
REVEL
Uncertain
0.29
Sift
Benign
0.51
T;D;.
Sift4G
Benign
0.66
T;T;.
Polyphen
0.82
P;.;.
Vest4
0.54
MutPred
0.57
Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);
MVP
0.42
ClinPred
0.074
T
GERP RS
1.7
Varity_R
0.079
gMVP
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1276301012; hg19: chr15-32322823; API