NM_001353108.3:c.555G>C

Variant names:

• chr3-134537268-G-C
• rs114108011
• NM_001353108.3:c.555G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PP3_Strong BP6_Very_Strong BS1 BS2

The NM_001353108.3(CEP63):​c.555G>C​(p.Gln185His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,583,514 control chromosomes in the GnomAD database, including 571 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.020 (53 hom., cov: 32)
  • Exomes 𝑓: 0.021 (518 hom.)
• Consequence: CEP63 NM_001353108.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.68
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 3-134537268-G-C is Benign according to our data. Variant chr3-134537268-G-C is described in ClinVar as Benign. ClinVar VariationId is 128709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0201 (3055/152282) while in subpopulation NFE AF = 0.0256 (1744/68024). AF 95% confidence interval is 0.0246. There are 53 homozygotes in GnomAd4. There are 1628 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 53 AR gene

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

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3058 AN: 152164 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0837

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.0213 AC: 5348 AN: 251168 AF XY: 0.0213

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00547

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0865

Gnomad NFE exome AF: 0.0256

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0209 AC: 29918 AN: 1431232 Hom.: 518 Cov.: 24 AF XY: 0.0204 AC XY: 14577 AN XY: 713974

African (AFR) AF: 0.00289 AC: 95 AN: 32892

American (AMR) AF: 0.00604 AC: 270 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0102 AC: 264 AN: 25932

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39566

South Asian (SAS) AF: 0.00286 AC: 245 AN: 85670

European-Finnish (FIN) AF: 0.0851 AC: 4543 AN: 53368

Middle Eastern (MID) AF: 0.00578 AC: 33 AN: 5714

European-Non Finnish (NFE) AF: 0.0215 AC: 23342 AN: 1084024

Other (OTH) AF: 0.0189 AC: 1125 AN: 59388

GnomAD4 genome AF: 0.0201 AC: 3055 AN: 152282 Hom.: 53 Cov.: 32 AF XY: 0.0219 AC XY: 1628 AN XY: 74452

African (AFR) AF: 0.00363 AC: 151 AN: 41550

American (AMR) AF: 0.0108 AC: 166 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4826

European-Finnish (FIN) AF: 0.0837 AC: 888 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0256 AC: 1744 AN: 68024

Other (OTH) AF: 0.0132 AC: 28 AN: 2116

Alfa AF: 0.0211 Hom.: 44

Bravo AF: 0.0135

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0186 AC: 160

ExAC AF: 0.0219 AC: 2657

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0208

EpiControl AF: 0.0187

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.21	T
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	0.029	D
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.73	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
Polyphen		1.0	D
Vest4		0.82
MutPred		0.32		Gain of catalytic residue at I183 (P = 0.1009)
MPC		0.22
ClinPred		0.014	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.48
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
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

Other links and lift over

dbSNP: rs114108011; hg19: chr3-134256110;