chr5-123378350-T-C

Variant names:

• chr5-123378350-T-C
• rs61744334
• NM_001375405.1:c.2182A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001375405.1(CEP120):​c.2182A>G​(p.Ser728Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,606,672 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (10 hom., cov: 30)
  • Exomes 𝑓: 0.00078 (9 hom.)
• Consequence: CEP120 NM_001375405.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.01
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023715496).
• BP6: Variant 5-123378350-T-C is Benign according to our data. Variant chr5-123378350-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 476163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00704 (1069/151808) while in subpopulation AFR AF = 0.0246 (1017/41382). AF 95% confidence interval is 0.0233. There are 10 homozygotes in GnomAd4. There are 554 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP120	NM_001375405.1	MANE Select	c.2182A>G	p.Ser728Gly	missense	Exon 15 of 20	NP_001362334.1	Q8N960-1
	CEP120	NM_153223.4		c.2182A>G	p.Ser728Gly	missense	Exon 16 of 21	NP_694955.2	Q8N960-1
	CEP120	NM_001166226.2		c.2104A>G	p.Ser702Gly	missense	Exon 15 of 20	NP_001159698.1	Q8N960-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP120	ENST00000306467.10	TSL:5 MANE Select	c.2182A>G	p.Ser728Gly	missense	Exon 15 of 20	ENSP00000303058.6	Q8N960-1
	CEP120	ENST00000508138.5	TSL:1	n.*1754A>G		non_coding_transcript_exon	Exon 18 of 23	ENSP00000422234.1	D6R8Z4
	CEP120	ENST00000513565.6	TSL:1	n.*1392A>G		non_coding_transcript_exon	Exon 15 of 21	ENSP00000422089.2	Q8N960-3

Frequencies

GnomAD3 genomes AF: 0.00692 AC: 1050 AN: 151688 Hom.: 9 Cov.: 30

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

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: 0.000265

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00186 AC: 456 AN: 245084 AF XY: 0.00134

Gnomad AFR exome AF: 0.0244

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.00168

GnomAD4 exome AF: 0.000782 AC: 1138 AN: 1454864 Hom.: 9 Cov.: 31 AF XY: 0.000734 AC XY: 531 AN XY: 723886

African (AFR) AF: 0.0243 AC: 794 AN: 32740

American (AMR) AF: 0.00160 AC: 69 AN: 43244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25914

East Asian (EAS) AF: 0.00 AC: 0 AN: 39388

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00262 AC: 15 AN: 5732

European-Non Finnish (NFE) AF: 0.000151 AC: 167 AN: 1109282

Other (OTH) AF: 0.00150 AC: 90 AN: 60042

GnomAD4 genome AF: 0.00704 AC: 1069 AN: 151808 Hom.: 10 Cov.: 30 AF XY: 0.00747 AC XY: 554 AN XY: 74184

African (AFR) AF: 0.0246 AC: 1017 AN: 41382

American (AMR) AF: 0.00184 AC: 28 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67934

Other (OTH) AF: 0.00285 AC: 6 AN: 2102

Alfa AF: 0.00283 Hom.: 5

Bravo AF: 0.00788

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00231 AC: 280

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000222

EpiControl AF: 0.000241

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Short-rib thoracic dysplasia 13 with or without polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0078	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.0
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.024
Sift	Benign	0.35	T
Sift4G	Benign	0.37	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.21
MPC		0.067
ClinPred		0.0080	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.070
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs61744334; hg19: chr5-122714044; COSMIC: COSV107387469;