4-625771-G-T

Variant names:

• chr4-625771-G-T
• rs79826315
• NM_000283.4:c.145G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000496514.6(PDE6B):​c.145G>T​(p.Asp49Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,613,498 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00098 (12 hom.)
• Consequence: PDE6B ENST00000496514.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.99
• Publications: 7 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 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007756084).
• BP6: Variant 4-625771-G-T is Benign according to our data. Variant chr4-625771-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00129 (197/152354) while in subpopulation EAS AF = 0.0292 (151/5178). AF 95% confidence interval is 0.0254. There are 5 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000496514.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6B	NM_000283.4	MANE Select	c.145G>T	p.Asp49Tyr	missense	Exon 1 of 22	NP_000274.3
	PDE6B	NM_001440547.1		c.145G>T	p.Asp49Tyr	missense	Exon 1 of 22	NP_001427476.1
	PDE6B	NM_001145291.2		c.145G>T	p.Asp49Tyr	missense	Exon 1 of 22	NP_001138763.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6B	ENST00000496514.6	TSL:1 MANE Select	c.145G>T	p.Asp49Tyr	missense	Exon 1 of 22	ENSP00000420295.1
	PDE6B	ENST00000255622.10	TSL:1	c.145G>T	p.Asp49Tyr	missense	Exon 1 of 22	ENSP00000255622.6

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152236 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0289

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00280 AC: 699 AN: 249576 AF XY: 0.00260

Gnomad AFR exome AF: 0.000434

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0322

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.000517

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000978 AC: 1429 AN: 1461144 Hom.: 12 Cov.: 33 AF XY: 0.000973 AC XY: 707 AN XY: 726910

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.0000894 AC: 4 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0269 AC: 1068 AN: 39696

South Asian (SAS) AF: 0.000394 AC: 34 AN: 86254

European-Finnish (FIN) AF: 0.000852 AC: 45 AN: 52816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000171 AC: 190 AN: 1111914

Other (OTH) AF: 0.00141 AC: 85 AN: 60380

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152354 Hom.: 5 Cov.: 33 AF XY: 0.00156 AC XY: 116 AN XY: 74504

African (AFR) AF: 0.000216 AC: 9 AN: 41590

American (AMR) AF: 0.000719 AC: 11 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0292 AC: 151 AN: 5178

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68028

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00131 Hom.: 8

Bravo AF: 0.00181

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00315 AC: 382

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Congenital stationary night blindness autosomal dominant 2 (1)
-	-	1	not specified (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.014
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.62	P
Vest4		0.28
MVP		0.81
MPC		0.28
ClinPred		0.043	T
GERP RS		5.0
PromoterAI		-0.011	Neutral
Varity_R		0.37
gMVP		0.50
Mutation Taster		=99/1	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: rs79826315; hg19: chr4-619560;