rs747831095
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_018249.6(CDK5RAP2):c.3097delG(p.Val1033SerfsTer41) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,992 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_018249.6 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: 0.0000657 AC: 10AN: 152140Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251292Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135800
GnomAD4 exome AF: 0.0000486 AC: 71AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.0000564 AC XY: 41AN XY: 727224
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152140Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74316
ClinVar
Submissions by phenotype
Microcephaly 3, primary, autosomal recessive Pathogenic:3
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Inborn genetic diseases Pathogenic:1
The c.3097delG (p.V1033Sfs*41) alteration, located in exon 23 (coding exon 23) of the CDK5RAP2 gene, consists of a deletion of one nucleotide at position 3097, causing a translational frameshift with a predicted alternate stop codon after 41 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of <0.01% (12/282696) total alleles studied. The highest observed frequency was 0.01% (12/129012) of European (non-Finnish) alleles. This variant was detected in trans with another CDK5RAP2 pathogenic variant in a male with moderate learning difficulties, severe behavioral problems, microcephaly, and multiple cafe-au-lait macules on his skin (Pagnamenta, 2015). Based on the available evidence, this alteration is classified as pathogenic. -
not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Val1033Serfs*41) in the CDK5RAP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDK5RAP2 are known to be pathogenic (PMID: 15793586, 20460369, 26436113). This variant is present in population databases (rs747831095, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with CDK5RAP2-related conditions (PMID: 27761245). ClinVar contains an entry for this variant (Variation ID: 209966). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at