CEP63 p.Gln185His

Variant names:

• chr3-134537268-G-T
• NM_001353108.3:c.555G>T
• CEP63 p.Gln185His

Your query was ambiguous. Multiple possible variants found:

• chr3-134537268-G-T
• chr3-134537268-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001353108.3(CEP63):​c.555G>T​(p.Gln185His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEP63 NM_001353108.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.68
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.555G>T	p.Gln185His	missense splice_region	Exon 6 of 15	NP_001340037.1	Q96MT8-1
	CEP63	NM_025180.5		c.555G>T	p.Gln185His	missense splice_region	Exon 7 of 16	NP_079456.2
	CEP63	NM_001353109.1		c.555G>T	p.Gln185His	missense splice_region	Exon 6 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.555G>T	p.Gln185His	missense splice_region	Exon 6 of 15	ENSP00000502085.1	Q96MT8-1
	CEP63	ENST00000383229.8	TSL:1	c.555G>T	p.Gln185His	missense splice_region	Exon 6 of 13	ENSP00000372716.3	Q96MT8-2
	CEP63	ENST00000332047.10	TSL:1	c.555G>T	p.Gln185His	missense splice_region	Exon 6 of 12	ENSP00000328382.5	Q96MT8-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.28
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.033	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.48
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-134256110;