13-24905828-T-G

Variant names:

• chr13-24905828-T-G
• NM_018451.5:c.2210A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018451.5(CENPJ):​c.2210A>C​(p.Asp737Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CENPJ NM_018451.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.386

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]

ACMG classification

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=0.03353539).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPJ	NM_018451.5	c.2210A>C	p.Asp737Ala	missense_variant	Exon 7 of 17	ENST00000381884.9	NP_060921.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPJ	ENST00000381884.9	c.2210A>C	p.Asp737Ala	missense_variant	Exon 7 of 17	1	NM_018451.5	ENSP00000371308.4
CENPJ	ENST00000616936.4	n.2210A>C		non_coding_transcript_exon_variant	Exon 7 of 16	1		ENSP00000477511.1
CENPJ	ENST00000545981.6	n.2210A>C		non_coding_transcript_exon_variant	Exon 7 of 18	2		ENSP00000441090.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CENPJ protein function. This variant has not been reported in the literature in individuals affected with CENPJ-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 737 of the CENPJ protein (p.Asp737Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.77
DANN	Benign	0.15
DEOGEN2	Benign	0.0025	.;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.37	T;T;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.034	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N;N;.
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.080	.;N;N
REVEL	Benign	0.0060
Sift	Benign	0.39	.;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.045
MutPred		0.24		Loss of ubiquitination at K742 (P = 0.0382);Loss of ubiquitination at K742 (P = 0.0382);Loss of ubiquitination at K742 (P = 0.0382);
MVP		0.14
MPC		0.15
ClinPred		0.022	T
GERP RS		1.0
Varity_R		0.035
gMVP		0.066

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-25479966;