rs28675771

Variant names:

• chr4-670119-A-G
• rs28675771
• NM_000283.4:c.*12A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000283.4(PDE6B):​c.*12A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.636 in 1,610,026 control chromosomes in the GnomAD database, including 329,275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26789 hom., cov: 34)
  • Exomes 𝑓: 0.64 (302486 hom.)
• Consequence: PDE6B NM_000283.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.47
• Publications: 14 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 (BayesDel_noAF=-0.9).
• BP6: Variant 4-670119-A-G is Benign according to our data. Variant chr4-670119-A-G is described in ClinVar as Benign. ClinVar VariationId is 349400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6B	NM_000283.4	MANE Select	c.*12A>G		3_prime_UTR	Exon 22 of 22	NP_000274.3
	PDE6B	NM_001440547.1		c.2512A>G	p.Met838Val	missense	Exon 22 of 22	NP_001427476.1
	PDE6B	NM_001350154.3		c.1675A>G	p.Met559Val	missense	Exon 20 of 20	NP_001337083.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6B	ENST00000496514.6	TSL:1 MANE Select	c.*12A>G		3_prime_UTR	Exon 22 of 22	ENSP00000420295.1
	PDE6B	ENST00000255622.10	TSL:1	c.*12A>G		3_prime_UTR	Exon 22 of 22	ENSP00000255622.6
	PDE6B	ENST00000461490.1	TSL:3	c.352A>G	p.Met118Val	missense	Exon 5 of 5	ENSP00000417178.1

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88823 AN: 151942 Hom.: 26767 Cov.: 34

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.679

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.575

GnomAD2 exomes AF: 0.615 AC: 154433 AN: 251034 AF XY: 0.621

Gnomad AFR exome AF: 0.441

Gnomad AMR exome AF: 0.617

Gnomad ASJ exome AF: 0.535

Gnomad EAS exome AF: 0.426

Gnomad FIN exome AF: 0.678

Gnomad NFE exome AF: 0.656

Gnomad OTH exome AF: 0.624

GnomAD4 exome AF: 0.641 AC: 935064 AN: 1457966 Hom.: 302486 Cov.: 33 AF XY: 0.643 AC XY: 466429 AN XY: 725460

African (AFR) AF: 0.433 AC: 14455 AN: 33402

American (AMR) AF: 0.617 AC: 27599 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.537 AC: 14008 AN: 26094

East Asian (EAS) AF: 0.404 AC: 16035 AN: 39686

South Asian (SAS) AF: 0.652 AC: 56202 AN: 86168

European-Finnish (FIN) AF: 0.676 AC: 35665 AN: 52758

Middle Eastern (MID) AF: 0.607 AC: 3490 AN: 5754

European-Non Finnish (NFE) AF: 0.659 AC: 730524 AN: 1109114

Other (OTH) AF: 0.615 AC: 37086 AN: 60294

GnomAD4 genome AF: 0.585 AC: 88886 AN: 152060 Hom.: 26789 Cov.: 34 AF XY: 0.584 AC XY: 43398 AN XY: 74312

African (AFR) AF: 0.447 AC: 18530 AN: 41464

American (AMR) AF: 0.597 AC: 9111 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 1840 AN: 3472

East Asian (EAS) AF: 0.445 AC: 2302 AN: 5178

South Asian (SAS) AF: 0.639 AC: 3082 AN: 4824

European-Finnish (FIN) AF: 0.679 AC: 7191 AN: 10584

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.659 AC: 44759 AN: 67954

Other (OTH) AF: 0.571 AC: 1202 AN: 2106

Alfa AF: 0.631 Hom.: 72456

Bravo AF: 0.568

Asia WGS AF: 0.522 AC: 1818 AN: 3478

EpiCase AF: 0.648

EpiControl AF: 0.660

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Congenital stationary night blindness autosomal dominant 2 (2)
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa 40 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.31
DANN	Benign	0.64
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs28675771; hg19: chr4-663908; COSMIC: COSV55324901; COSMIC: COSV55324901;