chr15-78580960-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000745.4(CHRNA5):c.256G>T(p.Val86Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,618 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
CHRNA5
NM_000745.4 missense, splice_region
NM_000745.4 missense, splice_region
Scores
7
8
4
Splicing: ADA: 0.9900
2
Clinical Significance
Conservation
PhyloP100: 8.10
Genes affected
CHRNA5 (HGNC:1959): (cholinergic receptor nicotinic alpha 5 subunit) The protein encoded by this gene is a nicotinic acetylcholine receptor subunit and a member of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. These receptors are thought to be heteropentamers composed of separate but similar subunits. Defects in this gene have been linked to susceptibility to lung cancer type 2 (LNCR2).[provided by RefSeq, Jun 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNA5 | NM_000745.4 | c.256G>T | p.Val86Leu | missense_variant, splice_region_variant | 2/6 | ENST00000299565.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNA5 | ENST00000299565.9 | c.256G>T | p.Val86Leu | missense_variant, splice_region_variant | 2/6 | 1 | NM_000745.4 | P1 | |
CHRNA5 | ENST00000394802.4 | c.73G>T | p.Val25Leu | missense_variant, splice_region_variant | 1/5 | 3 | |||
CHRNA5 | ENST00000559554.5 | c.256G>T | p.Val86Leu | missense_variant, splice_region_variant | 2/6 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.0000363 AC: 9AN: 248186Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134554
GnomAD3 exomes
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GnomAD4 exome AF: 0.00000343 AC: 5AN: 1459618Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726188
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GnomAD4 genome ? Cov.: 33
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33
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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 submitter | clinical testing | Ambry Genetics | Oct 20, 2023 | The c.256G>T (p.V86L) alteration is located in exon 2 (coding exon 2) of the CHRNA5 gene. This alteration results from a G to T substitution at nucleotide position 256, causing the valine (V) at amino acid position 86 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Benign
T;D
Polyphen
D;.
Vest4
MutPred
Gain of ubiquitination at K89 (P = 0.115);Gain of ubiquitination at K89 (P = 0.115);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at