12-14978073-A-G

Position:

• chr12-14978073-A-G

Variant summary

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

The NM_006205.3(PDE6H):​c.61A>G​(p.Lys21Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDE6H NM_006205.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.37

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]

ACMG classification

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	c.61A>G	p.Lys21Glu	missense_variant	2/4	ENST00000266395.3	NP_006196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE6H	ENST00000266395.3	c.61A>G	p.Lys21Glu	missense_variant	2/4	1	NM_006205.3	ENSP00000266395.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2023

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 21 of the PDE6H protein (p.Lys21Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PDE6H-related conditions. ClinVar contains an entry for this variant (Variation ID: 1044479). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.92	T
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.24
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.034	D
Polyphen		0.77	P
Vest4		0.62
MutPred		0.46		Loss of methylation at K21 (P = 9e-04);
MVP		0.80
MPC		0.018
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1864624045; hg19: chr12-15131007;