rs121909505
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000751.3(CHRND):c.234G>A(p.Trp78Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,228 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
CHRND
NM_000751.3 stop_gained
NM_000751.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 8.98
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 Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 2-232527436-G-A is Pathogenic according to our data. Variant chr2-232527436-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232527436-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRND | NM_000751.3 | c.234G>A | p.Trp78Ter | stop_gained | 3/12 | ENST00000258385.8 | |
CHRND | NM_001311195.2 | c.-38G>A | 5_prime_UTR_variant | 3/10 | |||
CHRND | NM_001311196.2 | c.-38G>A | 5_prime_UTR_variant | 3/12 | |||
CHRND | NM_001256657.2 | c.198+762G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRND | ENST00000258385.8 | c.234G>A | p.Trp78Ter | stop_gained | 3/12 | 1 | NM_000751.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151994Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251296Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135848
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461234Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 726966
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Lethal multiple pterygium syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2008 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 15, 2022 | This sequence change creates a premature translational stop signal (p.Trp78*) in the CHRND gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHRND are known to be pathogenic (PMID: 11435464, 25264167). This variant is present in population databases (rs121909505, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with severe fetal akinesia sequence disorder (PMID: 18252226). ClinVar contains an entry for this variant (Variation ID: 18368). For these reasons, this variant has been classified as Pathogenic. - |
Congenital myasthenic syndrome 3B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 15, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2017 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A
Vest4
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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