3-134559428-C-A

Variant names:

• chr3-134559428-C-A
• rs1127826
• NM_001353108.3:c.1952C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001353108.3(CEP63):​c.1952C>A​(p.Ser651*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CEP63 NM_001353108.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.0004225
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.279
• Publications: 23 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288700 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0758 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.1952C>A	p.Ser651*	stop_gained splice_region	Exon 14 of 15	NP_001340037.1	Q96MT8-1
	CEP63	NM_025180.5		c.1952C>A	p.Ser651*	stop_gained splice_region	Exon 15 of 16	NP_079456.2
	CEP63	NM_001353109.1		c.1814C>A	p.Ser605*	stop_gained splice_region	Exon 13 of 14	NP_001340038.1	A0A804HIX3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP63	ENST00000675561.1	MANE Select	c.1952C>A	p.Ser651*	stop_gained splice_region	Exon 14 of 15	ENSP00000502085.1	Q96MT8-1
	CEP63	ENST00000383229.8	TSL:1	c.1468-1949C>A		intron	N/A	ENSP00000372716.3	Q96MT8-2
	CEP63	ENST00000332047.10	TSL:1	c.1330-1949C>A		intron	N/A	ENSP00000328382.5	Q96MT8-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249468 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459646 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726272

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110432

Other (OTH) AF: 0.00 AC: 0 AN: 60296

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	36
DANN	Uncertain	0.98
Eigen	Benign	0.18
Eigen_PC	Benign	-0.062
FATHMM_MKL	Benign	0.51	D
PhyloP100		0.28
Vest4		0.18
GERP RS		-2.9
Mutation Taster		=28/172	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00042
dbscSNV1_RF	Benign	0.38
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: rs1127826; hg19: chr3-134278270;