21-46436076-T-C
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_006031.6(PCNT):āc.8924T>Cā(p.Leu2975Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00194 in 1,613,046 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0060 ( 8 hom., cov: 33)
Exomes š: 0.0015 ( 17 hom. )
Consequence
PCNT
NM_006031.6 missense
NM_006031.6 missense
Scores
3
7
8
Clinical Significance
Conservation
PhyloP100: 4.75
Genes affected
PCNT (HGNC:16068): (pericentrin) The protein encoded by this gene binds to calmodulin and is expressed in the centrosome. It is an integral component of the pericentriolar material (PCM). The protein contains a series of coiled-coil domains and a highly conserved PCM targeting motif called the PACT domain near its C-terminus. The protein interacts with the microtubule nucleation component gamma-tubulin and is likely important to normal functioning of the centrosomes, cytoskeleton, and cell-cycle progression. Mutations in this gene cause Seckel syndrome-4 and microcephalic osteodysplastic primordial dwarfism type II. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.007478386).
BP6
Variant 21-46436076-T-C is Benign according to our data. Variant chr21-46436076-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 159682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46436076-T-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00603 (919/152290) while in subpopulation AFR AF= 0.0154 (639/41564). AF 95% confidence interval is 0.0144. There are 8 homozygotes in gnomad4. There are 458 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 8 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PCNT | NM_006031.6 | c.8924T>C | p.Leu2975Pro | missense_variant | 39/47 | ENST00000359568.10 | NP_006022.3 | |
PCNT | NM_001315529.2 | c.8333T>C | p.Leu2778Pro | missense_variant | 39/47 | NP_001302458.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PCNT | ENST00000359568.10 | c.8924T>C | p.Leu2975Pro | missense_variant | 39/47 | 1 | NM_006031.6 | ENSP00000352572.5 |
Frequencies
GnomAD3 genomes AF: 0.00603 AC: 918AN: 152172Hom.: 8 Cov.: 33
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GnomAD3 exomes AF: 0.00292 AC: 720AN: 246774Hom.: 6 AF XY: 0.00251 AC XY: 336AN XY: 134128
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GnomAD4 exome AF: 0.00151 AC: 2205AN: 1460756Hom.: 17 Cov.: 33 AF XY: 0.00143 AC XY: 1039AN XY: 726748
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GnomAD4 genome AF: 0.00603 AC: 919AN: 152290Hom.: 8 Cov.: 33 AF XY: 0.00615 AC XY: 458AN XY: 74480
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 07, 2020 | - - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Microcephalic osteodysplastic primordial dwarfism type II Benign:3
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 14, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 28, 2022 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Benign
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at