rs114280473

Positions:

• chr5-123378398-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001375405.1(CEP120):​c.2134C>T​(p.Leu712Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00408 in 1,570,510 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0041 (22 hom.)
• Consequence: CEP120 NM_001375405.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:2 B:4
• Conservation: PhyloP100: 5.47

Genes affected

CEP120 (HGNC:26690): (centrosomal protein 120) This gene encodes a protein that functions in the microtubule-dependent coupling of the nucleus and the centrosome. A similar protein in mouse plays a role in both interkinetic nuclear migration, which is a characteristic pattern of nuclear movement in neural progenitors, and in neural progenitor self-renewal. Mutations in this gene are predicted to result in neurogenic defects. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072216988).
• BP6: Variant 5-123378398-G-A is Benign according to our data. Variant chr5-123378398-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 446145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-123378398-G-A is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00396 (584/147584) while in subpopulation NFE AF= 0.00473 (318/67268). AF 95% confidence interval is 0.0043. There are 1 homozygotes in gnomad4. There are 326 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP120	NM_001375405.1	c.2134C>T	p.Leu712Phe	missense_variant	15/20	ENST00000306467.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP120	ENST00000306467.10	c.2134C>T	p.Leu712Phe	missense_variant	15/20	5	NM_001375405.1	P1

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 584 AN: 147486 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000857

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00313

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0186

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00473

Gnomad OTH AF: 0.00394

GnomAD3 exomes AF: 0.00377 AC: 914 AN: 242590 Hom.: 1 AF XY: 0.00377 AC XY: 496 AN XY: 131458

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0162

Gnomad NFE exome AF: 0.00441

Gnomad OTH exome AF: 0.00275

GnomAD4 exome AF: 0.00410 AC: 5830 AN: 1422926 Hom.: 22 Cov.: 31 AF XY: 0.00403 AC XY: 2853 AN XY: 708804

Gnomad4 AFR exome AF: 0.000599

Gnomad4 AMR exome AF: 0.00149

Gnomad4 ASJ exome AF: 0.0000793

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.0152

Gnomad4 NFE exome AF: 0.00441

Gnomad4 OTH exome AF: 0.00269

GnomAD4 genome AF: 0.00396 AC: 584 AN: 147584 Hom.: 1 Cov.: 30 AF XY: 0.00455 AC XY: 326 AN XY: 71680

Gnomad4 AFR AF: 0.000855

Gnomad4 AMR AF: 0.00313

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0186

Gnomad4 NFE AF: 0.00473

Gnomad4 OTH AF: 0.00390

Alfa AF: 0.00379 Hom.: 1

Bravo AF: 0.00286

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00353 AC: 429

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Uncertain:2 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2 Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CEP120: BS1, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2020	This variant is associated with the following publications: (PMID: 30988386, 27208211, 27270415) -

Joubert syndrome 31 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 09, 2018

- -

CEP120-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 14, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Short-rib thoracic dysplasia 13 with or without polydactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;T;.;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0072	T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Pathogenic	2.9	M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.95
MVP		0.80
MPC		0.45
ClinPred		0.065	T
GERP RS		5.8
Varity_R		0.65
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs114280473; hg19: chr5-122714092;