rs587777694

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000313546.8(POC1B):​c.810+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,447,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

POC1B
ENST00000313546.8 splice_donor

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.79
Variant links:
Genes affected
POC1B (HGNC:30836): (POC1 centriolar protein B) POC1 proteins contain an N-terminal WD40 domain and a C-terminal coiled coil domain and are part of centrosomes. They play an important role in basal body and cilia formation. This gene encodes one of the two POC1 proteins found in humans. Mutation in this gene result in autosomal-recessive cone-rod dystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-89470360-C-A is Pathogenic according to our data. Variant chr12-89470360-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 155771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-89470360-C-A is described in Lovd as [Pathogenic]. Variant chr12-89470360-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POC1BNM_172240.3 linkuse as main transcriptc.810+1G>T splice_donor_variant ENST00000313546.8 NP_758440.1
POC1BNM_001199777.2 linkuse as main transcriptc.684+1G>T splice_donor_variant NP_001186706.1
POC1BNR_037659.2 linkuse as main transcriptn.790+1G>T splice_donor_variant, non_coding_transcript_variant
POC1BNR_037660.2 linkuse as main transcriptn.849+1G>T splice_donor_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POC1BENST00000313546.8 linkuse as main transcriptc.810+1G>T splice_donor_variant 1 NM_172240.3 ENSP00000323302 P1Q8TC44-1

Frequencies

GnomAD3 genomes
AF:
0.0000527
AC:
8
AN:
151750
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000265
AC:
6
AN:
226694
Hom.:
0
AF XY:
0.0000486
AC XY:
6
AN XY:
123554
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000564
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000110
AC:
142
AN:
1296074
Hom.:
0
Cov.:
28
AF XY:
0.0000972
AC XY:
62
AN XY:
637744
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000139
Gnomad4 OTH exome
AF:
0.0000191
GnomAD4 genome
AF:
0.0000527
AC:
8
AN:
151750
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74126
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000642
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:4
Pathogenic, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 10, 2023Observed with another POC1B variant in multiple unrelated patients with progressive retinopathy referred for genetic testing at GeneDx and in published literature (PMID: 25018096, 34065499); Published functional studies demonstrate a damaging effect with skipping of exon 7 or exons 6 and 7 resulting in a null allele (PMID: 25018096); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34065499, 25018096) -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 11, 2023This sequence change affects a donor splice site in intron 7 of the POC1B gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587777694, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with POC1B related conditions (PMID: 25018096, 34065499). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 155771). Studies have shown that disruption of this splice site results in skipping of exon 6 and skipping of exon 6-7 and introduces a premature termination codon (PMID: 25018096). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Cone-rod dystrophy 20 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 07, 2014- -
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Univ. Regensburg, Univ. RegensburgJan 01, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
30
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.98
FATHMM_MKL
Pathogenic
0.99
D
MutationTaster
Benign
1.0
D;D;D;D;D;D
GERP RS
5.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.87
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.99
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587777694; hg19: chr12-89864137; API