rs747045010

Variant names:

• chr12-94400920-G-A
• rs747045010
• NM_016122.3:c.479C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016122.3(CEP83):​c.479C>T​(p.Ser160Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000793 in 1,513,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S160S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000066 (0 hom.)
• Consequence: CEP83 NM_016122.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.45
• Publications: 0 publications found

Genes affected

CEP83 (HGNC:17966): (centrosomal protein 83) The protein encoded by this gene is a centriolar protein involved in primary cilium assembly. Defects in this gene have been associated with infantile nephronophthisis and intellectual disability. [provided by RefSeq, Oct 2016]

CEP83 Gene-Disease associations (from GenCC):

• nephronophthisis 18

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• nephronophthisis 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016122.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP83	NM_016122.3	MANE Select	c.479C>T	p.Ser160Leu	missense	Exon 6 of 17	NP_057206.2
	CEP83	NM_001042399.2		c.479C>T	p.Ser160Leu	missense	Exon 5 of 16	NP_001035858.1
	CEP83	NM_001346457.2		c.479C>T	p.Ser160Leu	missense	Exon 5 of 17	NP_001333386.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP83	ENST00000397809.10	TSL:1 MANE Select	c.479C>T	p.Ser160Leu	missense	Exon 6 of 17	ENSP00000380911.4
	CEP83	ENST00000339839.9	TSL:1	c.479C>T	p.Ser160Leu	missense	Exon 5 of 16	ENSP00000344655.5
	CEP83	ENST00000547232.5	TSL:1	n.380C>T		non_coding_transcript_exon	Exon 6 of 17	ENSP00000447783.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152046 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00000971 AC: 2 AN: 206024 AF XY: 0.00000885

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000202

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000661 AC: 9 AN: 1361492 Hom.: 0 Cov.: 24 AF XY: 0.00000889 AC XY: 6 AN XY: 674890

African (AFR) AF: 0.00 AC: 0 AN: 29848

American (AMR) AF: 0.00 AC: 0 AN: 34714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24156

East Asian (EAS) AF: 0.00 AC: 0 AN: 35352

South Asian (SAS) AF: 0.00 AC: 0 AN: 65880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5452

European-Non Finnish (NFE) AF: 0.00000755 AC: 8 AN: 1059754

Other (OTH) AF: 0.0000179 AC: 1 AN: 55910

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152046 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74266

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15256

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.000480 AC: 1 AN: 2084

Alfa AF: 0.0000301 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Nephronophthisis 18 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.31	T
PhyloP100		8.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.26
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.047	D
Polyphen		0.97	D
Vest4		0.83
MVP		0.83
MPC		0.42
ClinPred		0.77	D
GERP RS		5.8
Varity_R		0.21
gMVP		0.47
Mutation Taster		=62/38	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: rs747045010; hg19: chr12-94794696;