rs17402892

Positions:

• chr13-24905403-A-C

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.2635T>G​(p.Ser879Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,613,748 control chromosomes in the GnomAD database, including 14,414 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (908 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13506 hom.)
• Consequence: CENPJ NM_018451.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.371

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=0.0011765659).
• BP6: Variant 13-24905403-A-C is Benign according to our data. Variant chr13-24905403-A-C is described in ClinVar as [Benign]. Clinvar id is 21661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24905403-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CENPJ	NM_018451.5	c.2635T>G	p.Ser879Ala	missense_variant	7/17	ENST00000381884.9	NP_060921.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CENPJ	ENST00000381884.9	c.2635T>G	p.Ser879Ala	missense_variant	7/17	1	NM_018451.5	ENSP00000371308	P1
CENPJ	ENST00000616936.4	c.2635T>G	p.Ser879Ala	missense_variant, NMD_transcript_variant	7/16	1		ENSP00000477511
CENPJ	ENST00000545981.6	c.2635T>G	p.Ser879Ala	missense_variant, NMD_transcript_variant	7/18	2		ENSP00000441090

Frequencies

GnomAD3 genomes AF: 0.0998 AC: 15176 AN: 152066 Hom.: 909 Cov.: 32

Gnomad AFR AF: 0.0366

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.0918

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.0752

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.101

GnomAD3 exomes AF: 0.110 AC: 27671 AN: 251310 Hom.: 1775 AF XY: 0.112 AC XY: 15166 AN XY: 135816

Gnomad AFR exome AF: 0.0351

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.0801

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.131 AC: 191425 AN: 1461564 Hom.: 13506 Cov.: 34 AF XY: 0.130 AC XY: 94185 AN XY: 727086

Gnomad4 AFR exome AF: 0.0310

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.123

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.0825

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.0997 AC: 15169 AN: 152184 Hom.: 908 Cov.: 32 AF XY: 0.0976 AC XY: 7265 AN XY: 74412

Gnomad4 AFR AF: 0.0365

Gnomad4 AMR AF: 0.0915

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.00367

Gnomad4 SAS AF: 0.0748

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.0995

Alfa AF: 0.129 Hom.: 2192

Bravo AF: 0.0950

TwinsUK AF: 0.148 AC: 547

ALSPAC AF: 0.148 AC: 572

ESP6500AA AF: 0.0418 AC: 184

ESP6500EA AF: 0.138 AC: 1189

ExAC AF: 0.109 AC: 13276

Asia WGS AF: 0.0450 AC: 157 AN: 3478

EpiCase AF: 0.140

EpiControl AF: 0.141

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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 12, 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. -

Seckel syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	0.067
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.4
DANN	Benign	0.96
DEOGEN2	Benign	0.0058	.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.39	T;T;T
MetaRNN	Benign	0.0012	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.65	.;N;N
REVEL	Benign	0.073
Sift	Benign	0.21	.;T;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.0030	.;B;.
Vest4		0.032
MPC		0.10
ClinPred		0.00072	T
GERP RS		-0.95
Varity_R		0.031
gMVP		0.047

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: rs17402892; hg19: chr13-25479541; COSMIC: COSV67883550; COSMIC: COSV67883550;