chr12-94333494-A-C

Variant names:

• chr12-94333494-A-C
• rs150415429
• NM_016122.3:c.1565T>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_016122.3(CEP83):​c.1565T>G​(p.Leu522Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000238 in 1,613,174 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L522L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: CEP83 NM_016122.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.00
• 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: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• nephronophthisis 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007227689).
• BP6: Variant 12-94333494-A-C is Benign according to our data. Variant chr12-94333494-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541796.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0012 (182/152278) while in subpopulation AFR AF = 0.00431 (179/41564). AF 95% confidence interval is 0.00379. There are 0 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP83	NM_016122.3	MANE Select	c.1565T>G	p.Leu522Arg	missense	Exon 13 of 17	NP_057206.2	Q9Y592-1
	CEP83	NM_001042399.2		c.1565T>G	p.Leu522Arg	missense	Exon 12 of 16	NP_001035858.1	Q9Y592-1
	CEP83	NM_001346457.2		c.1565T>G	p.Leu522Arg	missense	Exon 12 of 17	NP_001333386.1	Q9Y592-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP83	ENST00000397809.10	TSL:1 MANE Select	c.1565T>G	p.Leu522Arg	missense	Exon 13 of 17	ENSP00000380911.4	Q9Y592-1
	CEP83	ENST00000339839.9	TSL:1	c.1565T>G	p.Leu522Arg	missense	Exon 12 of 16	ENSP00000344655.5	Q9Y592-1
	CEP83	ENST00000547232.5	TSL:1	n.1466T>G		non_coding_transcript_exon	Exon 13 of 17	ENSP00000447783.1	A0A338VFC5

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000342 AC: 85 AN: 248758 AF XY: 0.000245

Gnomad AFR exome AF: 0.00524

Gnomad AMR exome AF: 0.0000582

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: 0.000332

GnomAD4 exome AF: 0.000138 AC: 202 AN: 1460896 Hom.: 1 Cov.: 31 AF XY: 0.000111 AC XY: 81 AN XY: 726696

African (AFR) AF: 0.00524 AC: 175 AN: 33412

American (AMR) AF: 0.000269 AC: 12 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111646

Other (OTH) AF: 0.000199 AC: 12 AN: 60364

GnomAD4 genome AF: 0.00120 AC: 182 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74472

African (AFR) AF: 0.00431 AC: 179 AN: 41564

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000591 Hom.: 3

Bravo AF: 0.00144

ESP6500AA AF: 0.00712 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000464 AC: 56

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	CEP83-related disorder (1)
-	-	1	Nephronophthisis 18 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.23
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.0
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.043
Sift	Benign	0.82	T
Sift4G	Benign	0.74	T
Vest4		0.43
MVP		0.27
MPC		0.12
ClinPred		0.0052	T
GERP RS		3.5
Varity_R		0.14
gMVP		0.18
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150415429; hg19: chr12-94727270;