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rs149885751

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018451.5(CENPJ):c.2470A>T(p.Thr824Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,614,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

CENPJ
NM_018451.5 missense

Scores

1
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.280
Variant links:
Genes affected
CENPJ (HGNC:17272): (centromere protein J) This gene encodes a protein that belongs to the centromere protein family. During cell division, this protein plays a structural role in the maintenance of centrosome integrity and normal spindle morphology, and it is involved in microtubule disassembly at the centrosome. This protein can function as a transcriptional coactivator in the Stat5 signaling pathway, and also as a coactivator of NF-kappaB-mediated transcription, likely via its interaction with the coactivator p300/CREB-binding protein. Mutations in this gene are associated with primary autosomal recessive microcephaly, a disorder characterized by severely reduced brain size and cognitive disability. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.012545615).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CENPJNM_018451.5 linkuse as main transcriptc.2470A>T p.Thr824Ser missense_variant 7/17 ENST00000381884.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CENPJENST00000381884.9 linkuse as main transcriptc.2470A>T p.Thr824Ser missense_variant 7/171 NM_018451.5 P1Q9HC77-1
CENPJENST00000616936.4 linkuse as main transcriptc.2470A>T p.Thr824Ser missense_variant, NMD_transcript_variant 7/161 Q9HC77-2
CENPJENST00000545981.6 linkuse as main transcriptc.2470A>T p.Thr824Ser missense_variant, NMD_transcript_variant 7/182

Frequencies

GnomAD3 genomes
AF:
0.000230
AC:
35
AN:
152218
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000820
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000517
AC:
13
AN:
251434
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.000738
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000219
AC:
32
AN:
1461884
Hom.:
0
Cov.:
34
AF XY:
0.0000220
AC XY:
16
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.000836
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000295
AC:
45
AN:
152336
Hom.:
0
Cov.:
33
AF XY:
0.000376
AC XY:
28
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.00106
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Bravo
AF:
0.000291
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000824
AC:
10
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingInvitaeDec 30, 2021In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 158202). This variant has not been reported in the literature in individuals affected with CENPJ-related conditions. This variant is present in population databases (rs149885751, gnomAD 0.07%). This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 824 of the CENPJ protein (p.Thr824Ser). -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 02, 2016- -
Microcephaly 6, primary, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoOct 31, 2012- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.089
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.50
Cadd
Benign
1.7
Dann
Benign
0.72
Eigen
Benign
-0.86
Eigen_PC
Benign
-0.91
FATHMM_MKL
Benign
0.050
N
LIST_S2
Benign
0.71
T;T;T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.013
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.1
M;M;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.27
T
Sift4G
Benign
0.66
T;T;T
Polyphen
0.26
.;B;.
Vest4
0.069
MVP
0.79
MPC
0.14
ClinPred
0.023
T
GERP RS
1.7
Varity_R
0.053
gMVP
0.074

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs149885751; hg19: chr13-25479706; API