5-123385068-G-C

Variant names:

• chr5-123385068-G-C
• rs775080726
• NM_001375405.1:c.1646C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001375405.1(CEP120):​c.1646C>G​(p.Ala549Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A549V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEP120 NM_001375405.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.68
• Publications: 3 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-123385068-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446148.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP120	NM_001375405.1	c.1646C>G	p.Ala549Gly	missense_variant	Exon 11 of 20	ENST00000306467.10	NP_001362334.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP120	ENST00000306467.10	c.1646C>G	p.Ala549Gly	missense_variant	Exon 11 of 20	5	NM_001375405.1	ENSP00000303058.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.3	M;M;.;.
PhyloP100		7.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.3	N;N;N;D
REVEL	Benign	0.16
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		0.75	P;P;.;.
Vest4		0.68
MutPred		0.56		Gain of loop (P = 0.002);Gain of loop (P = 0.002);.;.;
MVP		0.53
MPC		0.091
ClinPred		0.76	D
GERP RS		5.6
Varity_R		0.52
gMVP		0.66
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs775080726; hg19: chr5-122720762;