chr12-88087872-C-G

Variant names:

• chr12-88087872-C-G
• NM_025114.4:c.4102G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025114.4(CEP290):​c.4102G>C​(p.Asp1368His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.88

Genes affected

CEP290 (HGNC:29021): (centrosomal protein 290) This gene encodes a protein with 13 putative coiled-coil domains, a region with homology to SMC chromosome segregation ATPases, six KID motifs, three tropomyosin homology domains and an ATP/GTP binding site motif A. The protein is localized to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation. Mutations in this gene have been associated with Joubert syndrome and nephronophthisis and the presence of antibodies against this protein is associated with several forms of cancer. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23150027).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.4102G>C	p.Asp1368His	missense_variant	Exon 32 of 54	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.4102G>C	p.Asp1368His	missense_variant	Exon 32 of 54	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 18

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 5 Uncertain:1

Feb 04, 2022

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This individual is heterozygous for the c.4102G>C variant in the CEP290 gene, which results in the amino acid substitution of aspartic acid to histidine at residue 1368, p.(Asp1368His). The variant has not been reported in any population databases (i.e. gnomAD v2.1.1, ESP or dbSNP). To our knowledge, this variant has not been previously reported in the literature or any disease specific databases. In silico analysis of pathogenicity (through Alamut Visual v2.13) using PolyPhen2, SIFT and MutationTaster suggest that this variant does not affect protein function and is likely to be benign. However, this analysis alone cannot be used to exclude pathogenicity. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines (evidence used: PM2, PM3_Supporting, BP4). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;.;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	.;.;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.078
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.90	.;.;P
Vest4		0.22
MutPred		0.21		.;.;Loss of stability (P = 0.0451);
MVP		0.75
MPC		0.25
ClinPred		0.65	D
GERP RS		5.5
Varity_R		0.056
gMVP		0.26

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-88481649;