4-55991942-C-G

Position:

• chr4-55991942-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_025009.5(CEP135):​c.1866C>G​(p.Ser622Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000766 in 1,305,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: CEP135 NM_025009.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.695

Genes affected

CEP135 (HGNC:29086): (centrosomal protein 135) This gene encodes a centrosomal protein, which acts as a scaffolding protein during early centriole biogenesis, and is also required for centriole-centriole cohesion during interphase. Mutations in this gene are associated with autosomal recessive primary microcephaly-8. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP135	NM_025009.5	c.1866C>G	p.Ser622Arg	missense_variant	15/26	ENST00000257287.5
CEP135	XM_006714055.4	c.1833C>G	p.Ser611Arg	missense_variant	15/26
CEP135	XM_005265788.5	c.795C>G	p.Ser265Arg	missense_variant	8/19
CEP135	XM_011534412.2	c.336C>G	p.Ser112Arg	missense_variant	5/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP135	ENST00000257287.5	c.1866C>G	p.Ser622Arg	missense_variant	15/26	1	NM_025009.5	P1
CEP135	ENST00000506202.1	n.1816C>G		non_coding_transcript_exon_variant	8/19	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.66e-7 AC: 1 AN: 1305482 Hom.: 0 Cov.: 25 AF XY: 0.00000153 AC XY: 1 AN XY: 652952

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000184

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 27, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.17
DANN	Benign	0.84
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.86	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.062
Sift	Benign	0.61	T
Sift4G	Benign	0.58	T
Polyphen		0.0020	B
Vest4		0.17
MutPred		0.15		Loss of ubiquitination at K624 (P = 0.1);
MVP		0.14
MPC		0.072
ClinPred		0.020	T
GERP RS		-4.6
Varity_R		0.060
gMVP		0.066

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.35		Position offset: -8

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

Publications

LitVar

Other links and lift over

dbSNP: rs376553815; hg19: chr4-56858108;