Variant 12-14978071-G-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_006205.3(PDE6H):c.59G>T(p.Arg20Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,364 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PDE6H
NM_006205.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.97

Variant links:

Genes affected

PDE6H (HGNC:8790): (phosphodiesterase 6H) This gene encodes the inhibitory (or gamma) subunit of the cone-specific cGMP phosphodiesterase, which is a tetramer composed of two catalytic chains (alpha and beta), and two inhibitory chains (gamma). It is specifically expressed in the retina, and is involved in the transmission and amplification of the visual signal. Mutations in this gene are associated with retinal cone dystrophy type 3A (RCD3A). [provided by RefSeq, Mar 2010]

PDE6H links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE6H	NM_006205.3 linkuse as main transcript	c.59G>T	p.Arg20Leu	missense_variant	2/4	ENST00000266395.3	NP_006196.1	Q13956

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE6H	ENST00000266395.3 linkuse as main transcript	c.59G>T	p.Arg20Leu	missense_variant	2/4	1	NM_006205.3	ENSP00000266395.2		Q13956

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461364

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727004

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 20, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PDE6H-related conditions. This variant is present in population databases (rs775561506, ExAC 0.006%). This sequence change replaces arginine with leucine at codon 20 of the PDE6H protein (p.Arg20Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.095

MetaRNN

Uncertain

0.71

MetaSVM

Benign

-0.77

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.0

REVEL

Benign

0.21

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0080

Polyphen

0.82

Vest4

0.65

MutPred

0.47

Loss of solvent accessibility (P = 6e-04);

MVP

0.81

MPC

0.043

ClinPred

0.99

GERP RS

5.2

Varity_R

0.72

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over