12-94400962-G-T

Variant names:

• chr12-94400962-G-T
• rs115988985
• NM_016122.3:c.437C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016122.3(CEP83):​c.437C>A​(p.Ala146Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000785 in 1,273,554 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A146V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: CEP83 NM_016122.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.41
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP83	NM_016122.3	c.437C>A	p.Ala146Asp	missense_variant	Exon 6 of 17	ENST00000397809.10	NP_057206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP83	ENST00000397809.10	c.437C>A	p.Ala146Asp	missense_variant	Exon 6 of 17	1	NM_016122.3	ENSP00000380911.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.85e-7 AC: 1 AN: 1273554 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 627250

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26988

American (AMR) AF: 0.00 AC: 0 AN: 24628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21032

East Asian (EAS) AF: 0.00 AC: 0 AN: 32740

South Asian (SAS) AF: 0.00 AC: 0 AN: 49112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5012

European-Non Finnish (NFE) AF: 9.85e-7 AC: 1 AN: 1015398

Other (OTH) AF: 0.00 AC: 0 AN: 51724

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	0.0040	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	.;.;T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	.;D;T;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-0.84	T
PhyloP100		4.4
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.46	N;N;.;N
REVEL	Benign	0.070
Sift	Benign	0.28	T;T;.;T
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.49	.;.;.;P
Vest4		0.52
MVP		0.82
MPC		0.34
ClinPred		0.81	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.24
Mutation Taster		=79/21	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: rs115988985; hg19: chr12-94794738;