12-94400962-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_016122.3(CEP83):​c.437C>T​(p.Ala146Val) variant causes a missense change. The variant allele was found at a frequency of 0.00175 in 1,425,758 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0092 (21 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (24 hom.)
• Consequence: CEP83 NM_016122.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.41
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003816247).
• BP6: Variant 12-94400962-G-A is Benign according to our data. Variant chr12-94400962-G-A is described in ClinVar as Benign. ClinVar VariationId is 474965.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00925 (1408/152248) while in subpopulation AFR AF = 0.0325 (1352/41552). AF 95% confidence interval is 0.0311. There are 21 homozygotes in GnomAd4. There are 676 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP83	NM_016122.3	MANE Select	c.437C>T	p.Ala146Val	missense	Exon 6 of 17	NP_057206.2
	CEP83	NM_001042399.2		c.437C>T	p.Ala146Val	missense	Exon 5 of 16	NP_001035858.1
	CEP83	NM_001346457.2		c.437C>T	p.Ala146Val	missense	Exon 5 of 17	NP_001333386.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP83	ENST00000397809.10	TSL:1 MANE Select	c.437C>T	p.Ala146Val	missense	Exon 6 of 17	ENSP00000380911.4
	CEP83	ENST00000339839.9	TSL:1	c.437C>T	p.Ala146Val	missense	Exon 5 of 16	ENSP00000344655.5
	CEP83	ENST00000547232.5	TSL:1	n.338C>T		non_coding_transcript_exon	Exon 6 of 17	ENSP00000447783.1

Frequencies

GnomAD3 genomes AF: 0.00923 AC: 1404 AN: 152130 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

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: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00222 AC: 384 AN: 172588 AF XY: 0.00159

Gnomad AFR exome AF: 0.0341

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000114

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.000855 AC: 1089 AN: 1273510 Hom.: 24 Cov.: 24 AF XY: 0.000730 AC XY: 458 AN XY: 627232

African (AFR) AF: 0.0350 AC: 944 AN: 26948

American (AMR) AF: 0.00150 AC: 37 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: 0.0000814 AC: 4 AN: 49112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46922

Middle Eastern (MID) AF: 0.00120 AC: 6 AN: 5012

European-Non Finnish (NFE) AF: 0.0000187 AC: 19 AN: 1015398

Other (OTH) AF: 0.00153 AC: 79 AN: 51718

GnomAD4 genome AF: 0.00925 AC: 1408 AN: 152248 Hom.: 21 Cov.: 33 AF XY: 0.00908 AC XY: 676 AN XY: 74456

African (AFR) AF: 0.0325 AC: 1352 AN: 41552

American (AMR) AF: 0.00288 AC: 44 AN: 15300

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68002

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00357 Hom.: 18

Bravo AF: 0.0108

ESP6500AA AF: 0.0327 AC: 118

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.00278 AC: 335

Asia WGS AF: 0.000290 AC: 1 AN: 3460

ClinVar

ClinVar submissions as Germline

Significance: Benign

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	0.14
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.94	T
PhyloP100		4.4
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.052
Sift	Benign	0.14	T
Sift4G	Benign	0.26	T
Polyphen		0.33	B
Vest4		0.35
MVP		0.81
MPC		0.20
ClinPred		0.011	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.14
Mutation Taster		=92/8	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; COSMIC: COSV99045918; COSMIC: COSV99045918;