5-123383015-G-C

Variant names:

• chr5-123383015-G-C
• rs150132498
• NM_001375405.1:c.1831C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001375405.1(CEP120):​c.1831C>G​(p.Arg611Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000278 in 1,440,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R611P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CEP120 NM_001375405.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.50
• Publications: 1 publications found

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]

CEP120 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Joubert syndrome 31

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short-rib thoracic dysplasia 13 with or without polydactyly

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with ocular defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375405.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP120	NM_001375405.1	MANE Select	c.1831C>G	p.Arg611Gly	missense	Exon 12 of 20	NP_001362334.1
	CEP120	NM_153223.4		c.1831C>G	p.Arg611Gly	missense	Exon 13 of 21	NP_694955.2
	CEP120	NM_001166226.2		c.1753C>G	p.Arg585Gly	missense	Exon 12 of 20	NP_001159698.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP120	ENST00000306467.10	TSL:5 MANE Select	c.1831C>G	p.Arg611Gly	missense	Exon 12 of 20	ENSP00000303058.6
	CEP120	ENST00000508138.5	TSL:1	n.*1403C>G		non_coding_transcript_exon	Exon 15 of 23	ENSP00000422234.1
	CEP120	ENST00000513565.6	TSL:1	n.*1041C>G		non_coding_transcript_exon	Exon 12 of 21	ENSP00000422089.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 246454 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: 0.00000278 AC: 4 AN: 1440398 Hom.: 0 Cov.: 27 AF XY: 0.00000418 AC XY: 3 AN XY: 717596

African (AFR) AF: 0.00 AC: 0 AN: 32988

American (AMR) AF: 0.00 AC: 0 AN: 43896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25850

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.00 AC: 0 AN: 84852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00000365 AC: 4 AN: 1094830

Other (OTH) AF: 0.00 AC: 0 AN: 59530

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Apr 09, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CEP120-related disease. This sequence change replaces arginine with glycine at codon 611 of the CEP120 protein (p.Arg611Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25").

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.5
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.12
Sift	Benign	0.050	D
Sift4G	Uncertain	0.052	T
Polyphen		0.53	P
Vest4		0.39
MVP		0.49
MPC		0.14
ClinPred		0.83	D
GERP RS		5.9
Varity_R		0.25
gMVP		0.24
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.49		Position offset: 0

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

Other links and lift over

dbSNP: rs150132498; hg19: chr5-122718709;