rs797045459

Variant names:

• chr3-134547391-TAGAC-T
• rs797045459
• NM_001353108.3:c.989_992delACAG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001353108.3(CEP63):​c.989_992delACAG​(p.Asp330ValfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,590 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CEP63 NM_001353108.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.48
• Publications: 0 publications found

Genes affected

CEP63 (HGNC:25815): (centrosomal protein 63) This gene encodes a protein with six coiled-coil domains. The protein is localized to the centrosome, a non-membraneous organelle that functions as the major microtubule-organizing center in animal cells. Several alternatively spliced transcript variants have been found, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

CEP63 Gene-Disease associations (from GenCC):

• Seckel syndrome 6

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288700 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-134547391-TAGAC-T is Pathogenic according to our data. Variant chr3-134547391-TAGAC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210705.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353108.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP63	NM_001353108.3	MANE Select	c.989_992delACAG	p.Asp330ValfsTer6	frameshift	Exon 9 of 15	NP_001340037.1
	CEP63	NM_025180.5		c.989_992delACAG	p.Asp330ValfsTer6	frameshift	Exon 10 of 16	NP_079456.2
	CEP63	NM_001042400.3		c.989_992delACAG	p.Asp330ValfsTer6	frameshift	Exon 9 of 13	NP_001035859.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP63	ENST00000675561.1	MANE Select	c.989_992delACAG	p.Asp330ValfsTer6	frameshift	Exon 9 of 15	ENSP00000502085.1
	CEP63	ENST00000383229.8	TSL:1	c.989_992delACAG	p.Asp330ValfsTer6	frameshift	Exon 9 of 13	ENSP00000372716.3
	CEP63	ENST00000332047.10	TSL:1	c.929+1106_929+1109delACAG		intron	N/A	ENSP00000328382.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461590 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 727116

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111752

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5

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

Other links and lift over

dbSNP: rs797045459; hg19: chr3-134266233;