chr11-117361836-C-G

Variant names:

• chr11-117361836-C-G
• rs61746874
• NM_014956.5:c.395C>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_014956.5(CEP164):​c.395C>G​(p.Ala132Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,614,200 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A132S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0058 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (7 hom.)
• Consequence: CEP164 NM_014956.5 missense, splice_region
• Scores: Splicing: ADA: 0.0001332
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.23
• Publications: 2 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=0.005328566).
• BP6: Variant 11-117361836-C-G is Benign according to our data. Variant chr11-117361836-C-G is described in ClinVar as Benign. ClinVar VariationId is 540296.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 = 0.00578 (880/152332) while in subpopulation AFR AF = 0.0202 (839/41578). AF 95% confidence interval is 0.019. There are 11 homozygotes in GnomAd4. There are 437 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.395C>G	p.Ala132Gly	missense splice_region	Exon 6 of 33	NP_055771.4
	CEP164	NM_001440949.1		c.395C>G	p.Ala132Gly	missense splice_region	Exon 6 of 33	NP_001427878.1
	CEP164	NM_001440950.1		c.395C>G	p.Ala132Gly	missense splice_region	Exon 6 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.395C>G	p.Ala132Gly	missense splice_region	Exon 6 of 33	ENSP00000278935.3	Q9UPV0-1
	CEP164	ENST00000957770.1		c.395C>G	p.Ala132Gly	missense splice_region	Exon 4 of 30	ENSP00000627829.1
	CEP164	ENST00000939969.1		c.395C>G	p.Ala132Gly	missense splice_region	Exon 7 of 32	ENSP00000610028.1

Frequencies

GnomAD3 genomes AF: 0.00577 AC: 878 AN: 152214 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0202

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: 0.0000441

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00150 AC: 377 AN: 251442 AF XY: 0.00111

Gnomad AFR exome AF: 0.0203

Gnomad AMR exome AF: 0.00113

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: 0.000652

GnomAD4 exome AF: 0.000605 AC: 884 AN: 1461868 Hom.: 7 Cov.: 31 AF XY: 0.000516 AC XY: 375 AN XY: 727236

African (AFR) AF: 0.0219 AC: 733 AN: 33474

American (AMR) AF: 0.00125 AC: 56 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112000

Other (OTH) AF: 0.00123 AC: 74 AN: 60394

GnomAD4 genome AF: 0.00578 AC: 880 AN: 152332 Hom.: 11 Cov.: 32 AF XY: 0.00587 AC XY: 437 AN XY: 74482

African (AFR) AF: 0.0202 AC: 839 AN: 41578

American (AMR) AF: 0.00163 AC: 25 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

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

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.000514 Hom.: 0

Bravo AF: 0.00660

ESP6500AA AF: 0.0189 AC: 83

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00171 AC: 208

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.074
Sift	Benign	0.35	T
Sift4G	Benign	0.27	T
Polyphen		0.34	B
Vest4		0.23
MVP		0.52
MPC		0.22
ClinPred		0.0059	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.027
gMVP		0.11
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.030
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: rs61746874; hg19: chr11-117232552;