rs138732534

chr13-24912851-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_018451.5(CENPJ):c.175A>G(p.Thr59Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,614,238 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CENPJ NM_018451.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.0820

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 Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.004066795).
• BP6: Variant 13-24912851-T-C is Benign according to our data. Variant chr13-24912851-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158196.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00146 (223/152352) while in subpopulation AFR AF= 0.0052 (216/41574). AF 95% confidence interval is 0.00463. There are 1 homozygotes in gnomad4. There are 102 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPJ	NM_018451.5	c.175A>G	p.Thr59Ala	missense_variant	2/17	ENST00000381884.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPJ	ENST00000381884.9	c.175A>G	p.Thr59Ala	missense_variant	2/17	1	NM_018451.5	P1
CENPJ	ENST00000616936.4	c.175A>G	p.Thr59Ala	missense_variant, NMD_transcript_variant	2/16	1
CENPJ	ENST00000545981.6	c.175A>G	p.Thr59Ala	missense_variant, NMD_transcript_variant	2/18	2

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 220 AN: 152234 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000318 AC: 80 AN: 251428 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135882

Gnomad AFR exome AF: 0.00449

Gnomad AMR exome AF: 0.000145

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000112 AC: 164 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.0000990 AC XY: 72 AN XY: 727242

Gnomad4 AFR exome AF: 0.00418

Gnomad4 AMR exome AF: 0.000112

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: 0.00000270

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152352 Hom.: 1 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74504

Gnomad4 AFR AF: 0.00520

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000247 Hom.: 0

Bravo AF: 0.00151

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000412 AC: 50

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 08, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 14, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Microcephaly 6, primary, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

CENPJ-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	1.4
Dann	Benign	0.41
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.55	T;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.0070	.;B;.
Vest4		0.042
MVP		0.30
MPC		0.12
ClinPred		0.010	T
GERP RS		-4.2
Varity_R		0.024
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs138732534; hg19: chr13-25486989;