rs114396665

Variant names:

• chr11-117381771-C-A
• rs114396665
• NM_014956.5:c.1480C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-117381771-C-A
• chr11-117381771-C-T

Variant summary

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

The NM_014956.5(CEP164):​c.1480C>A​(p.Pro494Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,603,380 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P494R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0065 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (7 hom.)
• Consequence: CEP164 NM_014956.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0460
• Publications: 3 publications found

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]

CEP164 Gene-Disease associations (from GenCC):

• CEP164-related ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• nephronophthisis 15

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• Senior-Loken syndrome

  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=0.003118813).
• BP6: Variant 11-117381771-C-A is Benign according to our data. Variant chr11-117381771-C-A is described in ClinVar as Benign. ClinVar VariationId is 540297.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 = 0.0065 (990/152240) while in subpopulation AFR AF = 0.0227 (944/41524). AF 95% confidence interval is 0.0215. There are 15 homozygotes in GnomAd4. There are 482 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014956.5. 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
	CEP164	NM_014956.5	MANE Select	c.1480C>A	p.Pro494Thr	missense	Exon 13 of 33	NP_055771.4
	CEP164	NM_001440949.1		c.1489C>A	p.Pro497Thr	missense	Exon 13 of 33	NP_001427878.1
	CEP164	NM_001440950.1		c.1480C>A	p.Pro494Thr	missense	Exon 13 of 33	NP_001427879.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP164	ENST00000278935.8	TSL:1 MANE Select	c.1480C>A	p.Pro494Thr	missense	Exon 13 of 33	ENSP00000278935.3	Q9UPV0-1
	CEP164	ENST00000957770.1		c.1411C>A	p.Pro471Thr	missense	Exon 10 of 30	ENSP00000627829.1
	CEP164	ENST00000939969.1		c.1402C>A	p.Pro468Thr	missense	Exon 13 of 32	ENSP00000610028.1

Frequencies

GnomAD3 genomes AF: 0.00649 AC: 988 AN: 152122 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00153 AC: 341 AN: 222628 AF XY: 0.00119

Gnomad AFR exome AF: 0.0231

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000726

GnomAD4 exome AF: 0.000676 AC: 981 AN: 1451140 Hom.: 7 Cov.: 30 AF XY: 0.000583 AC XY: 420 AN XY: 720824

African (AFR) AF: 0.0244 AC: 812 AN: 33248

American (AMR) AF: 0.00126 AC: 55 AN: 43598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25816

East Asian (EAS) AF: 0.00 AC: 0 AN: 39320

South Asian (SAS) AF: 0.0000950 AC: 8 AN: 84230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52474

Middle Eastern (MID) AF: 0.000705 AC: 4 AN: 5670

European-Non Finnish (NFE) AF: 0.0000208 AC: 23 AN: 1106868

Other (OTH) AF: 0.00132 AC: 79 AN: 59916

GnomAD4 genome AF: 0.00650 AC: 990 AN: 152240 Hom.: 15 Cov.: 33 AF XY: 0.00648 AC XY: 482 AN XY: 74436

African (AFR) AF: 0.0227 AC: 944 AN: 41524

American (AMR) AF: 0.00164 AC: 25 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68022

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00202 Hom.: 4

Bravo AF: 0.00740

ExAC AF: 0.00184 AC: 222

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	CEP164-related disorder (1)
-	-	1	Nephronophthisis 15 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.4
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.046
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.090
Sift	Uncertain	0.016	D
Sift4G	Benign	0.14	T
Polyphen		0.98	D
Vest4		0.25
MVP		0.48
MPC		0.40
ClinPred		0.018	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.22
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs114396665; hg19: chr11-117252487;