rs490262

chr11-117351876-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_014956.5(CEP164):c.281G>A(p.Ser94Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,613,052 control chromosomes in the GnomAD database, including 34,334 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S94S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.22 (3700 hom., cov: 30)
  • Exomes 𝑓: 0.20 (30634 hom.)
• Consequence: CEP164 NM_014956.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.937

Genes affected

CEP164 (HGNC:29182): (centrosomal protein 164) This gene encodes a centrosomal protein involved in microtubule organization, DNA damage response, and chromosome segregation. The encoded protein is required for assembly of primary cilia and localizes to mature centrioles. Defects in this gene are a cause of nephronophthisis-related ciliopathies. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_014956.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0023169518).
• BP6: Variant 11-117351876-G-A is Benign according to our data. Variant chr11-117351876-G-A is described in ClinVar as [Benign]. Clinvar id is 260481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351876-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP164	NM_014956.5	c.281G>A	p.Ser94Asn	missense_variant	5/33	ENST00000278935.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP164	ENST00000278935.8	c.281G>A	p.Ser94Asn	missense_variant	5/33	1	NM_014956.5	P1

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32711 AN: 151178 Hom.: 3690 Cov.: 30

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.211

GnomAD3 exomes AF: 0.211 AC: 53130 AN: 251368 Hom.: 6079 AF XY: 0.209 AC XY: 28334 AN XY: 135854

Gnomad AFR exome AF: 0.271

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.245

Gnomad EAS exome AF: 0.136

Gnomad SAS exome AF: 0.243

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.190

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.201 AC: 294485 AN: 1461762 Hom.: 30634 Cov.: 34 AF XY: 0.202 AC XY: 146847 AN XY: 727188

Gnomad4 AFR exome AF: 0.275

Gnomad4 AMR exome AF: 0.293

Gnomad4 ASJ exome AF: 0.247

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.244

Gnomad4 FIN exome AF: 0.145

Gnomad4 NFE exome AF: 0.196

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.216 AC: 32754 AN: 151290 Hom.: 3700 Cov.: 30 AF XY: 0.213 AC XY: 15735 AN XY: 73882

Gnomad4 AFR AF: 0.273

Gnomad4 AMR AF: 0.257

Gnomad4 ASJ AF: 0.235

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.139

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.209

Alfa AF: 0.198 Hom.: 7519

Bravo AF: 0.229

TwinsUK AF: 0.203 AC: 753

ALSPAC AF: 0.188 AC: 724

ESP6500AA AF: 0.275 AC: 1211

ESP6500EA AF: 0.200 AC: 1718

ExAC AF: 0.209 AC: 25382

Asia WGS AF: 0.193 AC: 673 AN: 3478

EpiCase AF: 0.189

EpiControl AF: 0.190

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Nephronophthisis 15 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	7.5
Dann	Benign	0.51
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.045	T;T;T;T;.;T
MetaRNN	Benign	0.0023	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.2	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.80	T;T;T;T;T;T
Sift4G	Benign	0.73	T;T;T;T;T;T
Polyphen		0.0	.;.;B;.;.;.
Vest4		0.044
MPC		0.095
ClinPred		0.0042	T
GERP RS		3.7
Varity_R		0.033
gMVP		0.046

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

Other links and lift over

dbSNP: rs490262; hg19: chr11-117222592; COSMIC: COSV54039014; COSMIC: COSV54039014;