12-6526306-AC-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014865.4(NCAPD2):βc.2508delCβ(p.Phe837SerfsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,410 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_014865.4 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: 151520Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251426Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135898
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461890Hom.: 0 Cov.: 41 AF XY: 0.0000165 AC XY: 12AN XY: 727248
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151520Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 73924
ClinVar
Submissions by phenotype
Microcephaly 21, primary, autosomal recessive Pathogenic:2
Variant summary: NCAPD2 c.2508delC (p.Phe837SerfsX36) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251426 control chromosomes. To our knowledge, no occurrence of c.2508delC in individuals affected with Microcephaly 21, Primary, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at