rs7336216

Positions:

• chr13-24912839-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018451.5(CENPJ):​c.187G>C​(p.Asp63His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,614,124 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (111 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (115 hom.)
• Consequence: CENPJ NM_018451.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.384

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020580292).
• BP6: Variant 13-24912839-C-G is Benign according to our data. Variant chr13-24912839-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 21660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24912839-C-G is described in Lovd as [Benign]. Variant chr13-24912839-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.067 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CENPJ	NM_018451.5	c.187G>C	p.Asp63His	missense_variant	2/17	ENST00000381884.9	NP_060921.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CENPJ	ENST00000381884.9	c.187G>C	p.Asp63His	missense_variant	2/17	1	NM_018451.5	ENSP00000371308.4
CENPJ	ENST00000616936.4	n.187G>C		non_coding_transcript_exon_variant	2/16	1		ENSP00000477511.1
CENPJ	ENST00000545981.6	n.187G>C		non_coding_transcript_exon_variant	2/18	2		ENSP00000441090.2

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 3010 AN: 152128 Hom.: 108 Cov.: 32

Gnomad AFR AF: 0.0690

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00550 AC: 1384 AN: 251418 Hom.: 47 AF XY: 0.00420 AC XY: 571 AN XY: 135882

Gnomad AFR exome AF: 0.0732

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00225 AC: 3291 AN: 1461878 Hom.: 115 Cov.: 32 AF XY: 0.00189 AC XY: 1378 AN XY: 727238

Gnomad4 AFR exome AF: 0.0780

Gnomad4 AMR exome AF: 0.00458

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000989

Gnomad4 OTH exome AF: 0.00518

GnomAD4 genome AF: 0.0198 AC: 3022 AN: 152246 Hom.: 111 Cov.: 32 AF XY: 0.0195 AC XY: 1450 AN XY: 74444

Gnomad4 AFR AF: 0.0691

Gnomad4 AMR AF: 0.00680

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00319 Hom.: 6

Bravo AF: 0.0234

ESP6500AA AF: 0.0665 AC: 293

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00672 AC: 816

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 07, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Microcephaly 6, primary, autosomal recessive Benign:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Microcephaly 6, primary, autosomal recessive;C3888212:Seckel syndrome 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 16, 2021

- -

Seckel syndrome 4 Benign:1

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	.;T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.82	T;T;T
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.0	.;N;N
REVEL	Benign	0.054
Sift	Uncertain	0.0080	.;D;D
Sift4G	Uncertain	0.048	D;D;D
Polyphen		0.88	.;P;.
Vest4		0.18
MVP		0.39
MPC		0.33
ClinPred		0.019	T
GERP RS		1.6
Varity_R		0.043
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs7336216; hg19: chr13-25486977;