chr4-654119-C-A

Variant names:

• chr4-654119-C-A
• rs121918579
• NM_000283.4:c.892C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000283.4(PDE6B):​c.892C>A​(p.Gln298Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q298P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDE6B NM_000283.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.547
• Publications: 0 publications found

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-AS1 (HGNC:40438): (PDE6B antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13707742).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000283.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6B	NM_000283.4	MANE Select	c.892C>A	p.Gln298Lys	missense	Exon 5 of 22	NP_000274.3
	PDE6B	NM_001440547.1		c.892C>A	p.Gln298Lys	missense	Exon 5 of 22	NP_001427476.1
	PDE6B	NM_001145291.2		c.892C>A	p.Gln298Lys	missense	Exon 5 of 22	NP_001138763.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6B	ENST00000496514.6	TSL:1 MANE Select	c.892C>A	p.Gln298Lys	missense	Exon 5 of 22	ENSP00000420295.1
	PDE6B	ENST00000255622.10	TSL:1	c.892C>A	p.Gln298Lys	missense	Exon 5 of 22	ENSP00000255622.6
	PDE6B	ENST00000467152.1	TSL:1	n.290C>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.55
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.15
Sift	Benign	0.76	T
Sift4G	Benign	0.40	T
Polyphen		0.012	B
Vest4		0.42
MutPred		0.50		Loss of helix (P = 0.0068)
MVP		0.81
MPC		0.24
ClinPred		0.67	D
GERP RS		5.1
Varity_R		0.22
gMVP		0.32
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs121918579; hg19: chr4-647908;