chr11-3667240-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_020402.4(CHRNA10):c.887C>T(p.Pro296Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000379 in 1,583,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
CHRNA10
NM_020402.4 missense
NM_020402.4 missense
Scores
13
4
2
Clinical Significance
Conservation
PhyloP100: 9.86
Genes affected
CHRNA10 (HGNC:13800): (cholinergic receptor nicotinic alpha 10 subunit) Predicted to enable acetylcholine-gated cation-selective channel activity. Acts upstream of or within positive regulation of cytosolic calcium ion concentration. Predicted to be located in membrane. Predicted to be active in cholinergic synapse and neuron projection. Predicted to be integral component of postsynaptic specialization membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.99
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNA10 | NM_020402.4 | c.887C>T | p.Pro296Leu | missense_variant | 4/5 | ENST00000250699.2 | |
CHRNA10 | NM_001303034.2 | c.269C>T | p.Pro90Leu | missense_variant | 4/5 | ||
CHRNA10 | NM_001303035.2 | c.269C>T | p.Pro90Leu | missense_variant | 4/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNA10 | ENST00000250699.2 | c.887C>T | p.Pro296Leu | missense_variant | 4/5 | 1 | NM_020402.4 | P1 | |
CHRNA10 | ENST00000534359.1 | c.340C>T | p.Arg114Cys | missense_variant | 4/5 | 1 | |||
CHRNA10 | ENST00000526599.1 | c.*658C>T | 3_prime_UTR_variant, NMD_transcript_variant | 4/5 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000498 AC: 1AN: 200954Hom.: 0 AF XY: 0.00000896 AC XY: 1AN XY: 111586
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GnomAD4 exome AF: 0.00000279 AC: 4AN: 1431364Hom.: 0 Cov.: 32 AF XY: 0.00000281 AC XY: 2AN XY: 711326
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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 | Jun 14, 2023 | The c.887C>T (p.P296L) alteration is located in exon 4 (coding exon 4) of the CHRNA10 gene. This alteration results from a C to T substitution at nucleotide position 887, causing the proline (P) at amino acid position 296 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
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Benign
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of disorder (P = 0.0402);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at