chr11-62909827-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5
The NM_000738.3(CHRM1):c.1274T>C(p.Phe425Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
CHRM1
NM_000738.3 missense
NM_000738.3 missense
Scores
12
3
4
Clinical Significance
Conservation
PhyloP100: 9.21
Genes affected
CHRM1 (HGNC:1950): (cholinergic receptor muscarinic 1) The muscarinic cholinergic receptors belong to a larger family of G protein-coupled receptors. The functional diversity of these receptors is defined by the binding of acetylcholine and includes cellular responses such as adenylate cyclase inhibition, phosphoinositide degeneration, and potassium channel mediation. Muscarinic receptors influence many effects of acetylcholine in the central and peripheral nervous system. The muscarinic cholinergic receptor 1 is involved in mediation of vagally-induced bronchoconstriction and in the acid secretion of the gastrointestinal tract. The gene encoding this receptor is localized to 11q13. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
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;
PP2
?
Missense variant where missense usually causes diseases, CHRM1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.929
PP5
?
Variant 11-62909827-A-G is Pathogenic according to our data. Variant chr11-62909827-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1098339.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRM1 | NM_000738.3 | c.1274T>C | p.Phe425Ser | missense_variant | 2/2 | ENST00000306960.4 | |
LOC124902683 | XR_007062701.1 | n.86+212A>G | intron_variant, non_coding_transcript_variant | ||||
CHRM1 | XM_011544742.3 | c.1274T>C | p.Phe425Ser | missense_variant | 2/2 | ||
LOC124902683 | XR_007062700.1 | n.86+212A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRM1 | ENST00000306960.4 | c.1274T>C | p.Phe425Ser | missense_variant | 2/2 | 1 | NM_000738.3 | P1 | |
ENST00000543624.1 | n.70+212A>G | intron_variant, non_coding_transcript_variant | 3 | ||||||
CHRM1 | ENST00000543973.1 | c.1274T>C | p.Phe425Ser | missense_variant | 3/3 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
See cases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli | Apr 26, 2021 | PM2_supporting;PM6_moderate;PP2_supporting;PP3_supporting - |
Flexion contracture Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | 3billion | Oct 25, 2021 | This variant is not observed in the gnomAD v2.1.1 dataset (PM2). It is inherited from the unaffected mother (3billion dataset). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CHRM1 related disorder (ClinVar ID:VCV001098339.1). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;.
Polyphen
D;.
Vest4
MutPred
Loss of stability (P = 0.0189);Loss of stability (P = 0.0189);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.