12-6526306-AC-A
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014865.4(NCAPD2):βc.2508delβ(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
Genomes: π 0.000013 ( 0 hom., cov: 32)
Exomes π: 0.000018 ( 0 hom. )
Consequence
NCAPD2
NM_014865.4 frameshift
NM_014865.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.606
Genes affected
NCAPD2 (HGNC:24305): (non-SMC condensin I complex subunit D2) Enables histone binding activity. Involved in mitotic chromosome condensation. Located in condensed chromosome; cytosol; and nucleoplasm. Part of condensin complex. Colocalizes with cytoplasm and nuclear chromosome. Implicated in primary autosomal recessive microcephaly. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-6526306-AC-A is Pathogenic according to our data. Variant chr12-6526306-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1339659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NCAPD2 | NM_014865.4 | c.2508del | p.Phe837SerfsTer36 | frameshift_variant | 20/32 | ENST00000315579.10 | NP_055680.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NCAPD2 | ENST00000315579.10 | c.2508del | p.Phe837SerfsTer36 | frameshift_variant | 20/32 | 1 | NM_014865.4 | ENSP00000325017 | P1 | |
| NCAPD2 | ENST00000382457.8 | c.2124del | p.Phe709SerfsTer36 | frameshift_variant | 17/21 | 5 | ENSP00000371895 | |||
| NCAPD2 | ENST00000542492.1 | n.441del | non_coding_transcript_exon_variant | 4/8 | 5 | |||||
| NCAPD2 | ENST00000539084.5 | c.*2203del | 3_prime_UTR_variant, NMD_transcript_variant | 19/31 | 2 | ENSP00000438495 |
Frequencies
GnomAD3 genomes 0.0000132 AC: 2AN: 151520Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251426Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135898
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GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461890Hom.: 0 Cov.: 41 AF XY: 0.0000165 AC XY: 12AN XY: 727248
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GnomAD4 genome 0.0000132 AC: 2AN: 151520Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 73924
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Microcephaly 21, primary, autosomal recessive Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 08, 2022 | 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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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at