7-16216110-CT-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_001101426.4(CRPPA):βc.1206delβ(p.Glu403LysfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,600,004 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β ).
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 33)
Exomes π: 0.000015 ( 0 hom. )
Consequence
CRPPA
NM_001101426.4 frameshift
NM_001101426.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.155
Genes affected
CRPPA (HGNC:37276): (CDP-L-ribitol pyrophosphorylase A) This gene encodes a 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase-like protein. Mutations in this gene are the cause of Walker-Warburg syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.111 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CRPPA | NM_001101426.4 | c.1206del | p.Glu403LysfsTer24 | frameshift_variant | 9/10 | ENST00000407010.7 | NP_001094896.1 | |
| CRPPA-AS1 | NR_038947.1 | n.118+5511del | intron_variant, non_coding_transcript_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CRPPA | ENST00000407010.7 | c.1206del | p.Glu403LysfsTer24 | frameshift_variant | 9/10 | 5 | NM_001101426.4 | ENSP00000385478 | P1 | |
| CRPPA-AS1 | ENST00000438573.5 | n.116+5511del | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000819 AC: 2AN: 244220Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 132266
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GnomAD4 exome AF: 0.0000145 AC: 21AN: 1447846Hom.: 0 Cov.: 26 AF XY: 0.0000153 AC XY: 11AN XY: 720622
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GnomAD4 genome 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74322
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7 (MIM#614643) and muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 7 (MIM#616052). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated D-ribitol-5-phosphate cytidylyltransferase C-terminal domain (NCBI conserved domain). (I) 0704 - Another protein truncating variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Glu439Ter) variant has been classified once as pathogenic and has been described to be in trans with a pathogenic variant (ClinVar). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at