13-24882581-C-CAT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_018451.5(CENPJ):c.*595_*596insAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00637 in 153,598 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0064 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0052 (0 hom.)
• Consequence: CENPJ NM_018451.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.127

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]

RNF17 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 13-24882581-C-CAT is Benign according to our data. Variant chr13-24882581-C-CAT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 311590.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00638 (972/152242) while in subpopulation NFE AF= 0.00994 (676/68016). AF 95% confidence interval is 0.00932. There are 4 homozygotes in gnomad4. There are 470 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPJ	NM_018451.5	c.*595_*596insAT		3_prime_UTR_variant	17/17	ENST00000381884.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPJ	ENST00000381884.9	c.*595_*596insAT		3_prime_UTR_variant	17/17	1	NM_018451.5	P1
CENPJ	ENST00000616936.4	c.*1266_*1267insAT		3_prime_UTR_variant, NMD_transcript_variant	16/16	1

Frequencies

GnomAD3 genomes AF: 0.00639 AC: 972 AN: 152126 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.00914

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00992

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00516 AC: 7 AN: 1356 Hom.: 0 Cov.: 0 AF XY: 0.00404 AC XY: 3 AN XY: 742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00649

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00499

Gnomad4 OTH exome AF: 0.0200

GnomAD4 genome AF: 0.00638 AC: 972 AN: 152242 Hom.: 4 Cov.: 31 AF XY: 0.00631 AC XY: 470 AN XY: 74432

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000833

Gnomad4 FIN AF: 0.00914

Gnomad4 NFE AF: 0.00994

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00783 Hom.: 1

Bravo AF: 0.00558

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	CENPJ: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2021	- -

Primary Microcephaly, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Seckel syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs570468323; hg19: chr13-25456719;