10-49646651-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_020549.5(CHAT):c.1258C>T(p.Arg420Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,822 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 Likely pathogenic (★★).
Frequency
Consequence
NM_020549.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461592Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727108
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74370
ClinVar
Submissions by phenotype
Familial infantile myasthenia Pathogenic:3
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Congenital myasthenic syndrome Pathogenic:1
Variant summary: CHAT c.1258C>T (p.Arg420Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 1607038 control chromosomes in the gnomAD database (v4.1 dataset). This frequency is not significantly higher than estimated for a pathogenic variant in CHAT causing Congenital Myasthenic Syndrome (0.00079), allowing no conclusion about variant significance. c.1258C>T has been reported in the literature in a compound heterozygous individual affected with Congenital Myasthenic Syndrome (Ohno_2001). Authors of this study also reported experimental evidence evaluating an impact on protein function, and demonstrated markedly reduced CHAT expression in COS cells, and significantly impaired catalytic efficiency (Ohno_2001). The following publication have been ascertained in the context of this evaluation (PMID: 11172068). ClinVar contains an entry for this variant (Variation ID: 17514). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at