rs138675304

chr13-24899558-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018451.5(CENPJ):c.2852A>G(p.Gln951Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000547 in 1,613,910 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.00037 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (6 hom.)
• Consequence: CENPJ NM_018451.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 3.88

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008300751).
• BP6: Variant 13-24899558-T-C is Benign according to our data. Variant chr13-24899558-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158205.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000374 (57/152382) while in subpopulation SAS AF= 0.00435 (21/4830). AF 95% confidence interval is 0.00291. There are 1 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPJ	NM_018451.5	c.2852A>G	p.Gln951Arg	missense_variant	9/17	ENST00000381884.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPJ	ENST00000381884.9	c.2852A>G	p.Gln951Arg	missense_variant	9/17	1	NM_018451.5	P1
CENPJ	ENST00000418179.1	c.98A>G	p.Gln33Arg	missense_variant	2/4	1
CENPJ	ENST00000616936.4	c.2852A>G	p.Gln951Arg	missense_variant, NMD_transcript_variant	9/16	1
CENPJ	ENST00000545981.6	c.2852A>G	p.Gln951Arg	missense_variant, NMD_transcript_variant	9/18	2

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 57 AN: 152264 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000845 AC: 212 AN: 250926 Hom.: 2 AF XY: 0.00111 AC XY: 150 AN XY: 135668

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00467

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000353

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000565 AC: 826 AN: 1461528 Hom.: 6 Cov.: 31 AF XY: 0.000726 AC XY: 528 AN XY: 727066

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00512

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000253

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152382 Hom.: 1 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74526

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000330 Hom.: 0

Bravo AF: 0.000264

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000931 AC: 113

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Microcephaly 6, primary, autosomal recessive Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 02, 2014	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 31, 2016

- -

Seckel syndrome 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0083	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M;M;.
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.46	T
Sift4G	Uncertain	0.045	D;D;D
Polyphen		0.66	.;P;.
Vest4		0.37
MVP		0.68
MPC		0.34
ClinPred		0.019	T
GERP RS		5.3
Varity_R		0.13
gMVP		0.062

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

Other links and lift over

dbSNP: rs138675304; hg19: chr13-25473696;