4-625651-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000283.4(PDE6B):c.25C>T(p.Arg9Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R9Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: PDE6B NM_000283.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.23

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019117296).
• BP6: Variant 4-625651-C-T is Benign according to our data. Variant chr4-625651-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 968558.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE6B	NM_000283.4	c.25C>T	p.Arg9Trp	missense_variant	1/22	ENST00000496514.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE6B	ENST00000496514.6	c.25C>T	p.Arg9Trp	missense_variant	1/22	1	NM_000283.4	P3
PDE6B	ENST00000255622.10	c.25C>T	p.Arg9Trp	missense_variant	1/22	1		A1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000156 AC: 39 AN: 249410 Hom.: 0 AF XY: 0.000141 AC XY: 19 AN XY: 135002

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000520 AC: 76 AN: 1461404 Hom.: 0 Cov.: 32 AF XY: 0.0000399 AC XY: 29 AN XY: 727054

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000362 AC XY: 27 AN XY: 74484

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000846 Hom.: 0

Bravo AF: 0.000408

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000165 AC: 20

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

The c.25C>T (p.R9W) alteration is located in exon 1 (coding exon 1) of the PDE6B gene. This alteration results from a C to T substitution at nucleotide position 25, causing the arginine (R) at amino acid position 9 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	0.14
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.019	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.99	D;D
Vest4		0.14
MVP		0.89
MPC		0.26
ClinPred		0.098	T
GERP RS		4.1
Varity_R		0.25
gMVP		0.32

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

LitVar

Other links and lift over

dbSNP: rs140441389; hg19: chr4-619440;