1-179992122-G-A

Variant names:

• chr1-179992122-G-A
• rs189019668
• NM_014810.5:c.296G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014810.5(CEP350):​c.296G>A​(p.Arg99Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000396 in 1,550,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: CEP350 NM_014810.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04
• Publications: 2 publications found

Genes affected

CEP350 (HGNC:24238): (centrosomal protein 350) The product of this gene is a large protein with a CAP-Gly domain typically found in cytoskeleton-associated proteins. The encoded protein primarily localizes to the centrosome, a non-membraneous organelle that functions as the major microtubule-organizing center in animal cells. The encoded protein directly interacts with another large centrosomal protein and is required to anchor microtubules at the centrosome. It is also implicated in the regulation of a class of nuclear hormone receptors in the nucleus. Several alternatively spliced transcript variants have been found, but their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

ENSG00000303101 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.052229673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP350	NM_014810.5	c.296G>A	p.Arg99Gln	missense_variant	Exon 5 of 38	ENST00000367607.8	NP_055625.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP350	ENST00000367607.8	c.296G>A	p.Arg99Gln	missense_variant	Exon 5 of 38	1	NM_014810.5	ENSP00000356579.3

Frequencies

GnomAD3 genomes AF: 0.000231 AC: 35 AN: 151504 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000193

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000153 AC: 26 AN: 169578 AF XY: 0.000199

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000843

Gnomad FIN exome AF: 0.000110

Gnomad NFE exome AF: 0.000300

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000414 AC: 579 AN: 1399138 Hom.: 0 Cov.: 31 AF XY: 0.000406 AC XY: 281 AN XY: 692186

African (AFR) AF: 0.000130 AC: 4 AN: 30778

American (AMR) AF: 0.00 AC: 0 AN: 33646

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25058

East Asian (EAS) AF: 0.0000276 AC: 1 AN: 36186

South Asian (SAS) AF: 0.0000392 AC: 3 AN: 76596

European-Finnish (FIN) AF: 0.0000789 AC: 4 AN: 50692

Middle Eastern (MID) AF: 0.000530 AC: 3 AN: 5658

European-Non Finnish (NFE) AF: 0.000513 AC: 555 AN: 1082652

Other (OTH) AF: 0.000138 AC: 8 AN: 57872

GnomAD4 genome AF: 0.000231 AC: 35 AN: 151614 Hom.: 0 Cov.: 31 AF XY: 0.000189 AC XY: 14 AN XY: 74030

African (AFR) AF: 0.0000967 AC: 4 AN: 41344

American (AMR) AF: 0.0000657 AC: 1 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.000193 AC: 2 AN: 10382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000398 AC: 27 AN: 67918

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000358 Hom.: 0

Bravo AF: 0.000223

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000125 AC: 15

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.296G>A (p.R99Q) alteration is located in exon 5 (coding exon 4) of the CEP350 gene. This alteration results from a G to A substitution at nucleotide position 296, causing the arginine (R) at amino acid position 99 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0042	T;.;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.052	T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.2	M;.;.
PhyloP100		3.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.99	N;N;D
REVEL	Benign	0.056
Sift	Uncertain	0.011	D;D;T
Sift4G	Benign	0.39	T;D;D
Polyphen		1.0	D;P;.
Vest4		0.15
MVP		0.32
MPC		0.087
ClinPred		0.11	T
GERP RS		4.7
Varity_R		0.11
gMVP		0.063
Mutation Taster		=86/14	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: rs189019668; hg19: chr1-179961257; COSMIC: COSV62485830;