rs1734048235

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_000283.4(PDE6B):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000686 in 1,457,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PDE6B
NM_000283.4 start_lost

Scores

4
9
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.60

Publications

0 publications found
Variant links:
Genes affected
PDE6B (HGNC:8786): (phosphodiesterase 6B) Photon absorption triggers a signaling cascade in rod photoreceptors that activates cGMP phosphodiesterase (PDE), resulting in the rapid hydrolysis of cGMP, closure of cGMP-gated cation channels, and hyperpolarization of the cell. PDE is a peripheral membrane heterotrimeric enzyme made up of alpha, beta, and gamma subunits. This gene encodes the beta subunit. Mutations in this gene result in retinitis pigmentosa and autosomal dominant congenital stationary night blindness. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2009]
PDE6B Gene-Disease associations (from GenCC):
  • retinitis pigmentosa 40
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
  • congenital stationary night blindness autosomal dominant 2
    Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • congenital stationary night blindness
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • retinitis pigmentosa
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 66 codons. Genomic position: 625822. Lost 0.076 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PDE6BNM_000283.4 linkc.3G>A p.Met1? start_lost Exon 1 of 22 ENST00000496514.6 NP_000274.3 P35913-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PDE6BENST00000496514.6 linkc.3G>A p.Met1? start_lost Exon 1 of 22 1 NM_000283.4 ENSP00000420295.1 P35913-1
PDE6BENST00000255622.10 linkc.3G>A p.Met1? start_lost Exon 1 of 22 1 ENSP00000255622.6 P35913-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1457428
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
725400
show subpopulations
⚠️ 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:
33386
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26118
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39678
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86164
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53264
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
9.02e-7
AC:
1
AN:
1108102
Other (OTH)
AF:
0.00
AC:
0
AN:
60238
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Uncertain
0.040
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.32
.;T
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
-0.24
T
PhyloP100
5.6
PROVEAN
Benign
-1.2
N;N
REVEL
Uncertain
0.38
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.98
D;D
Vest4
0.88
MutPred
0.96
Gain of catalytic residue at M1 (P = 0.0368);Gain of catalytic residue at M1 (P = 0.0368);
MVP
0.87
ClinPred
1.0
D
GERP RS
5.0
PromoterAI
-0.036
Neutral
Varity_R
0.81
gMVP
0.49
Mutation Taster
=5/195
disease causing

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

Other links and lift over

dbSNP: rs1734048235; hg19: chr4-619418; API