NM_007186.6:c.73C>G

Variant names:

• chr20-35462440-C-G
• rs772742308
• NM_007186.6:c.73C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007186.6(CEP250):​c.73C>G​(p.Leu25Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,604,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L25L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CEP250 NM_007186.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27
• Publications: 0 publications found

Genes affected

CEP250 (HGNC:1859): (centrosomal protein 250) This gene encodes a core centrosomal protein required for centriole-centriole cohesion during interphase of the cell cycle. The encoded protein dissociates from the centrosomes when parental centrioles separate at the beginning of mitosis. The protein associates with and is phosphorylated by NIMA-related kinase 2, which is also associated with the centrosome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

CEP250 Gene-Disease associations (from GenCC):

• cone-rod dystrophy and hearing loss 2

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• retinitis pigmentosa

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: NO_KNOWN Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17710319).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007186.6. 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
	CEP250	NM_007186.6	MANE Select	c.73C>G	p.Leu25Val	missense	Exon 4 of 35	NP_009117.2
	CEP250	NM_001318219.1		c.-1827C>G		5_prime_UTR	Exon 2 of 33	NP_001305148.1	Q9BV73

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP250	ENST00000397527.6	TSL:5 MANE Select	c.73C>G	p.Leu25Val	missense	Exon 4 of 35	ENSP00000380661.1	Q9BV73-1
	CEP250	ENST00000446710.5	TSL:1	c.73C>G	p.Leu25Val	missense	Exon 4 of 7	ENSP00000398747.1	Q5JWS5
	CEP250	ENST00000706828.1		c.73C>G	p.Leu25Val	missense	Exon 4 of 36	ENSP00000516576.1	A0A9L9PXX3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452750 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721832

African (AFR) AF: 0.00 AC: 0 AN: 33318

American (AMR) AF: 0.00 AC: 0 AN: 43336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25926

East Asian (EAS) AF: 0.00 AC: 0 AN: 39304

South Asian (SAS) AF: 0.00 AC: 0 AN: 84652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107628

Other (OTH) AF: 0.00 AC: 0 AN: 60034

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.3
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.11
Sift	Benign	0.79	T
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.29
MutPred		0.25		Loss of helix (P = 0.0033)
MVP		0.40
MPC		0.62
ClinPred		0.73	D
GERP RS		5.1
PromoterAI		0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.065
Mutation Taster		=75/25	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: rs772742308; hg19: chr20-34050265;