11-65182883-T-TC
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005186.4(CAPN1):c.188dupC(p.Val64GlyfsTer103) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,604,096 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_005186.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151932Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1452164Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1AN XY: 721516
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151932Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74184
ClinVar
Submissions by phenotype
not provided Pathogenic:2
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 817644). This variant is also known as c.183_184insC. This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 31227335). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Val64Glyfs*103) in the CAPN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CAPN1 are known to be pathogenic (PMID: 27153400, 27320912). -
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27320912, 31227335) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at