NM_000440.3:c.998+1446C>T

Variant names:

• chr5-149913497-G-A
• rs30825
• NM_000440.3:c.998+1446C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000440.3(PDE6A):​c.998+1446C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 151,944 control chromosomes in the GnomAD database, including 29,433 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.62 (29433 hom., cov: 31)
• Consequence: PDE6A NM_000440.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00400
• Publications: 5 publications found

Genes affected

PDE6A (HGNC:8785): (phosphodiesterase 6A) This gene encodes the cyclic-GMP (cGMP)-specific phosphodiesterase 6A alpha subunit, expressed in cells of the retinal rod outer segment. The phosphodiesterase 6 holoenzyme is a heterotrimer composed of an alpha, beta, and two gamma subunits. cGMP is an important regulator of rod cell membrane current, and its dynamic concentration is established by phosphodiesterase 6A cGMP hydrolysis and guanylate cyclase cGMP synthesis. The protein is a subunit of a key phototransduction enzyme and participates in processes of transmission and amplification of the visual signal. Mutations in this gene have been identified as one cause of autosomal recessive retinitis pigmentosa. [provided by RefSeq, Jul 2008]

PDE6A Gene-Disease associations (from GenCC):

• PDE6A-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 43

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000440.3. 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
	PDE6A	NM_000440.3	MANE Select	c.998+1446C>T		intron	N/A	NP_000431.2	P16499
	PDE6A	NM_001410788.1		c.755+1446C>T		intron	N/A	NP_001397717.1	F1T0K3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6A	ENST00000255266.10	TSL:1 MANE Select	c.998+1446C>T		intron	N/A	ENSP00000255266.5	P16499
	PDE6A	ENST00000508173.5	TSL:1	n.1118+1446C>T		intron	N/A
	PDE6A	ENST00000890426.1		c.998+1446C>T		intron	N/A	ENSP00000560485.1

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93584 AN: 151824 Hom.: 29424 Cov.: 31

Gnomad AFR AF: 0.496

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.684

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.639

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.616 AC: 93634 AN: 151944 Hom.: 29433 Cov.: 31 AF XY: 0.615 AC XY: 45688 AN XY: 74248

African (AFR) AF: 0.496 AC: 20546 AN: 41392

American (AMR) AF: 0.653 AC: 9987 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 2372 AN: 3470

East Asian (EAS) AF: 0.481 AC: 2484 AN: 5164

South Asian (SAS) AF: 0.507 AC: 2441 AN: 4818

European-Finnish (FIN) AF: 0.707 AC: 7454 AN: 10542

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.682 AC: 46315 AN: 67956

Other (OTH) AF: 0.633 AC: 1336 AN: 2112

Alfa AF: 0.655 Hom.: 105420

Bravo AF: 0.608

Asia WGS AF: 0.501 AC: 1746 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.2
DANN	Benign	0.54
PhyloP100		0.0040
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: rs30825; hg19: chr5-149293060;