rs776218605
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PP3_StrongPP5_Moderate
The NM_000751.3(CHRND):āc.769T>Cā(p.Cys257Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000297 in 1,614,064 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 Pathogenic (ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.000031 ( 0 hom. )
Consequence
CHRND
NM_000751.3 missense
NM_000751.3 missense
Scores
10
6
1
Clinical Significance
Conservation
PhyloP100: 6.12
Genes affected
CHRND (HGNC:1965): (cholinergic receptor nicotinic delta subunit) The acetylcholine receptor of muscle has 5 subunits of 4 different types: 2 alpha and 1 each of beta, gamma and delta subunits. After acetylcholine binding, the receptor undergoes an extensive conformation change that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. Defects in this gene are a cause of multiple pterygium syndrome lethal type (MUPSL), congenital myasthenic syndrome slow-channel type (SCCMS), and congenital myasthenic syndrome fast-channel type (FCCMS). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a transmembrane_region Helical (size 24) in uniprot entity ACHD_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000751.3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
?
Variant 2-232530088-T-C is Pathogenic according to our data. Variant chr2-232530088-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 534526.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-232530088-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRND | NM_000751.3 | c.769T>C | p.Cys257Arg | missense_variant | 7/12 | ENST00000258385.8 | |
CHRND | NM_001256657.2 | c.724T>C | p.Cys242Arg | missense_variant | 6/11 | ||
CHRND | NM_001311196.2 | c.466T>C | p.Cys156Arg | missense_variant | 7/12 | ||
CHRND | NM_001311195.2 | c.239-1264T>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRND | ENST00000258385.8 | c.769T>C | p.Cys257Arg | missense_variant | 7/12 | 1 | NM_000751.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251396Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135890
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GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 727244
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Lethal multiple pterygium syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 257 of the CHRND protein (p.Cys257Arg). This variant is present in population databases (rs776218605, gnomAD 0.006%). This missense change has been observed in individual(s) with fetal akinesia deformation sequence (FADS) (PMID: 26578207). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 534526). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CHRND protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CHRND function (PMID: 26578207). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
1.0
.;D
Vest4
MutPred
0.89
.;Loss of catalytic residue at P256 (P = 0.0601);
MVP
MPC
0.90
ClinPred
D
GERP RS
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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