rs139046818

Variant names:

• chr12-94335597-G-A
• rs139046818
• NM_016122.3:c.1411C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_016122.3(CEP83):​c.1411C>T​(p.Leu471Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0176 in 1,562,332 control chromosomes in the GnomAD database, including 304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L471L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., cov: 32)
  • Exomes 𝑓: 0.018 (282 hom.)
• Consequence: CEP83 NM_016122.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.66
• Publications: 3 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 12-94335597-G-A is Benign according to our data. Variant chr12-94335597-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0119 (1812/152000) while in subpopulation NFE AF = 0.0211 (1435/67934). AF 95% confidence interval is 0.0202. There are 22 homozygotes in GnomAd4. There are 798 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

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.1411C>T	p.Leu471Leu	synonymous	Exon 12 of 17	NP_057206.2
	CEP83	NM_001042399.2		c.1411C>T	p.Leu471Leu	synonymous	Exon 11 of 16	NP_001035858.1
	CEP83	NM_001346457.2		c.1411C>T	p.Leu471Leu	synonymous	Exon 11 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.1411C>T	p.Leu471Leu	synonymous	Exon 12 of 17	ENSP00000380911.4
	CEP83	ENST00000339839.9	TSL:1	c.1411C>T	p.Leu471Leu	synonymous	Exon 11 of 16	ENSP00000344655.5
	CEP83	ENST00000547232.5	TSL:1	n.1312C>T		non_coding_transcript_exon	Exon 12 of 17	ENSP00000447783.1

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1812 AN: 151882 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00358

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00669

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.00285

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0116 AC: 2533 AN: 218410 AF XY: 0.0119

Gnomad AFR exome AF: 0.00281

Gnomad AMR exome AF: 0.00487

Gnomad ASJ exome AF: 0.00532

Gnomad EAS exome AF: 0.000188

Gnomad FIN exome AF: 0.00281

Gnomad NFE exome AF: 0.0198

Gnomad OTH exome AF: 0.00937

GnomAD4 exome AF: 0.0182 AC: 25618 AN: 1410332 Hom.: 282 Cov.: 26 AF XY: 0.0178 AC XY: 12532 AN XY: 702078

African (AFR) AF: 0.00312 AC: 99 AN: 31748

American (AMR) AF: 0.00485 AC: 196 AN: 40406

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 132 AN: 25446

East Asian (EAS) AF: 0.000444 AC: 17 AN: 38320

South Asian (SAS) AF: 0.00909 AC: 736 AN: 80924

European-Finnish (FIN) AF: 0.00349 AC: 184 AN: 52698

Middle Eastern (MID) AF: 0.00371 AC: 21 AN: 5662

European-Non Finnish (NFE) AF: 0.0218 AC: 23429 AN: 1076720

Other (OTH) AF: 0.0138 AC: 804 AN: 58408

GnomAD4 genome AF: 0.0119 AC: 1812 AN: 152000 Hom.: 22 Cov.: 32 AF XY: 0.0107 AC XY: 798 AN XY: 74292

African (AFR) AF: 0.00357 AC: 148 AN: 41480

American (AMR) AF: 0.00661 AC: 101 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4812

European-Finnish (FIN) AF: 0.00285 AC: 30 AN: 10528

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.0211 AC: 1435 AN: 67934

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.0175 Hom.: 15

Bravo AF: 0.0119

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Nephronophthisis 18 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.7
DANN	Benign	0.74
PhyloP100		3.7
Mutation Taster		=100/0	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: rs139046818; hg19: chr12-94729373; COSMIC: COSV100353332; COSMIC: COSV100353332;