NM_001375405.1:c.1684A>G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001375405.1(CEP120):c.1684A>G(p.Thr562Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000379 in 1,613,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. T562S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

CEP120
NM_001375405.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 4.81

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04665774).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00039 (570/1461442) while in subpopulation AMR AF= 0.000828 (37/44670). AF 95% confidence interval is 0.000617. There are 0 homozygotes in gnomad4_exome. There are 285 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP120	NM_001375405.1 link	c.1684A>G	p.Thr562Ala	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 link	c.1684A>G	p.Thr562Ala	missense_variant	Exon 11 of 20	5	NM_001375405.1	ENSP00000303058.6		Q8N960-1

Frequencies

GnomAD3 genomes

AF:

0.000271

AC:

AN:

151504

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000527

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000339

AC:

AN:

251052

Hom.:

AF XY:

0.000346

AC XY:

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000784

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000431

Gnomad OTH exome

AF:

0.000818

GnomAD4 exome

AF:

0.000390

AC:

570

AN:

1461442

Hom.:

Cov.:

AF XY:

0.000392

AC XY:

285

AN XY:

727028

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000828

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000447

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.000270

AC:

AN:

151622

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74080

show subpopulations

Gnomad4 AFR

AF:

0.000194

Gnomad4 AMR

AF:

0.000526

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000412

Hom.:

Bravo

AF:

0.000302

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000534

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

May 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1684A>G (p.T562A) alteration is located in exon 12 (coding exon 11) of the CEP120 gene. This alteration results from a A to G substitution at nucleotide position 1684, causing the threonine (T) at amino acid position 562 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Short-rib thoracic dysplasia 13 with or without polydactyly;C4540355:Joubert syndrome 31

Uncertain:1

Feb 28, 2023

Clinical Genomics Laboratory, Stanford Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Jul 25, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Short-rib thoracic dysplasia 13 with or without polydactyly

Uncertain:1

Jan 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 562 of the CEP120 protein (p.Thr562Ala). This variant is present in population databases (rs147277049, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with CEP120-related conditions. ClinVar contains an entry for this variant (Variation ID: 577784). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CEP120 protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

T;T;.;T

Eigen

Benign

-0.014

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.76

.;T;T;T

M_CAP

Benign

0.0085

MetaRNN

Benign

0.047

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;L;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.5

N;N;N;N

REVEL

Benign

0.045

Sift

Benign

0.29

T;T;T;T

Sift4G

Benign

0.59

T;T;T;T

Polyphen

0.028

B;B;.;.

Vest4

0.29

MVP

0.40

MPC

0.073

ClinPred

0.017

GERP RS

5.6

Varity_R

0.23

gMVP

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over