12-6495075-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PVS1_ModeratePP3_StrongBS1_Supporting
The NM_014865.4(NCAPD2):c.-23-1G>A variant causes a splice acceptor change. The variant allele was found at a frequency of 0.000105 in 1,613,736 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00041 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000074 ( 1 hom. )
Consequence
NCAPD2
NM_014865.4 splice_acceptor
NM_014865.4 splice_acceptor
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.71
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 Uncertain_significance. Variant got 5 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.03542558 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000407 (62/152310) while in subpopulation AFR AF= 0.00142 (59/41570). AF 95% confidence interval is 0.00113. There are 1 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NCAPD2 | NM_014865.4 | c.-23-1G>A | splice_acceptor_variant | ENST00000315579.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NCAPD2 | ENST00000315579.10 | c.-23-1G>A | splice_acceptor_variant | 1 | NM_014865.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000401 AC: 61AN: 152192Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000116 AC: 29AN: 251076Hom.: 0 AF XY: 0.0000884 AC XY: 12AN XY: 135690
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GnomAD4 exome AF: 0.0000739 AC: 108AN: 1461426Hom.: 1 Cov.: 30 AF XY: 0.0000646 AC XY: 47AN XY: 727036
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 19, 2022 | Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at